Methods and compositions for treating skin

ABSTRACT

A method for treating intact irritated or inflamed skin with a composition comprising at least one Histamine Receptor pathway inhibitor; at least one Lipoxygenase pathway inhibitor; at least one Cyclooxygenase pathway inhibitor and at least one Chemotaxis pathway inhibitor.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/743,500, filed Aug. 4, 2010, which claims priority fromPCT/US08/69323, filed Jul. 7, 2008, which claims priority fromProvisional Application Ser. No. 61/015,250, filed Dec. 20, 2007.

TECHNICAL FIELD

The invention is in the field of formulating compositions for treatingskin and the resulting skin care compositions.

BACKGROUND OF THE INVENTION

Skin is the largest and one of the most complex body organs. Itcomprises from about 15 to 20% of the entire body weight and serves as aprotective barrier to environmental toxins and assaults. Very few peopleare satisfied with their skin condition, particularly facial skin. Skincare product companies have made a big business out of treating commonskin maladies such as dryness, oiliness, uneven pigmentation, wrinkles,laxity and the like. Skin that is in good health is referred to asnormalized skin. The skin's immune response to environmental conditionssuch as excessive sun exposure, cold weather, wind, or cigarette smokecan have an effect on skin. In some cases skin may become irritated orinflamed—in other words the skin is no longer normalized. For yearscosmetics manufacturers have sold products for normalizing skin thatincluded ingredients believed to have anti-inflammatory or anti-irritantproperties. However, since there are a myriad of biological reactivepathways that contribute to skin inflammation and these products oftencontained ingredients that did not have any impact on any of thesereactive pathways, they were not often as effective as they could havebeen. For example, one immune response of assaulted tissue is histaminerelease, predominantly by basophilic cells. Another reactive pathwaythat contributes to skin inflammation is release of cyclooxygenase-2(also referred to as COX-2), an enzyme known to promote inflammation andpain. Yet another reactive pathway that contributes to skin inflammationis the release of an enzyme, phospholipase-2 (PLA-2) by cells and tissuesubjected to immune assaults. Current skin care products may or may notcontain ingredients that have inhibitory effects on these reactivepathways. Accordingly, such products may not be optimally effective innormalizing skin.

There is a need for compositions for normalizing skin, that is, treatingskin that may be inflamed, irritated, or in otherwise a less thanoptimal state of health, to obtain improvement.

It is an object of the invention to provide a method for formulatingproducts to normalize skin, or treating irritated or inflamed skin forimprovement. Such method includes identifying one or more reactivepathways that contribute to skin inflammation and selecting one or moreingredients that inhibit the pathways selected and formulating theselected ingredients into a composition that when topically appliedexhibits skin normalizing properties.

It is a further object to provide a method for normalizing skin, ortreating irritated or inflamed skin for improvement comprising applyingto the skin a composition that has been formulated by identifying aplurality of pathways that contribute to inflammation and selecting atleast one ingredient that inhibits each of the pathways identified andformulating the plurality of selected ingredients into a composition.

It is a further object of the invention to provide a composition fornormalizing skin or treating skin irritation or inflammation comprisinga plurality of ingredients that are selected to inhibit a plurality ofpathways that contribute to skin inflammation.

SUMMARY OF THE INVENTION

The invention is directed to a method for formulating compositions fornormalizing skin comprising identifying a plurality of pathways thatcontribute to skin inflammation, selecting ingredients that inhibit thepathways identified and formulating the selected ingredients into acomposition that when topically applied exhibits skin normalizingproperties.

The invention is also directed to a method for formulating compositionsfor treating skin irritation or inflammation comprising identifying aplurality of pathways that contribute to skin inflammation, selectingone or more ingredients that inhibit the pathways identified andformulating the selected ingredients into a composition that whentopically applied ameliorates the undesired effects of skin irritationor inflammation.

The invention is further directed to a method for normalizing skincomprising applying to the skin a composition that has been formulatedby identifying a plurality of pathways that contribute to inflammation,selecting ingredients that inhibit the pathways identified andformulating the selected ingredients into a composition that providesskin normalizing properties.

The invention is further directed to a method for treating irritated orinflamed skin comprising applying to the skin a composition that hasbeen formulated by identifying a plurality of pathways that contributeto skin inflammation, selecting ingredients that inhibit the pathwaysidentified and formulating the ingredients into a composition thatameliorates the adverse effects of skin irritation or inflammation.

The invention is also directed to a composition for normalizing skincomprising a plurality of ingredients that are selected to inhibit aplurality of pathways that contribute to skin inflammation.

The invention is also directed to a composition for treating skinirritation or inflammation comprising a plurality of ingredients thatare selected to inhibit a plurality of pathways that contribute to skininflammation.

DESCRIPTION OF THE FIGURE

The FIGURE compares the effectiveness of several compositions atinhibiting inflammation.

DETAILED DESCRIPTION I. Definitions

“Adhesion Pathway” is the pathway by which cells adhere to blood vesselsand other skin tissues when injury or immune challenge has occurred.

“Chemotaxis Pathway” means the pathway where chemical signals causeinflammatory cells to migrate toward the site in the body, such as skinor tissue, where immune challenge has occurred. If such inflammatorycells are prevented from migrating to the site of immune challenge theresulting damage that such cells provide to skin or tissues can bemitigated.

“Collagenase Pathway” means the pathway by which the enzyme collagenasebreaks down the peptide bonds in collagen and destroys extracellularstructures such as those found in bacteria or infiltrating lymphocytesat the sites of inflammation. The collagenases released will causetissue damage by breaking down collagen fibrils in the extra cellularmatrix.

“COX Pathway” means the pathway by which the cyclooxygenase (COX) enzyme(including but not limited to cyclooxygenase-2 or COX-2) convertsarachidonic acid and/or other fatty acids to prostaglandin orprostanoids which ultimately contributes to inflammation or pain inimmune challenged tissue such as skin.

“Elastase Pathway” means the pathway by which the enzyme elastasedegrades proteins including elastin that are found in bacteria and othermolecules. When the Elastase Pathway is triggered the cascade ofreactions contributes to inflammation or pain in immune challengedtissue such as skin. Elastase, a peptidase released from infiltratingneutrophils at the site of inflammation, will break down elastin, anelastic fiber that, together with collagen, helps determine themechanical properties of skin and other tissues. Inhibition of elastasewill minimize the damage that may be caused by infiltrating neutrophilswhich in turn will help preserve the integrity of the extra cellularmatrix.

“Histamine Pathway” means the pathway where the amino acid histidine isdecarboxylated to form histamine in response to immune challenge orother injury to tissue or skin. Histamine is a biogenic amine that issynthesized and stored in mast cells which reside primarily in the skin.Histamine plays a major role in the initiation of the inflammatorycascade. Upon stimulation, mast cells (and basophils) will release theirstored histamine which will bind to H1 receptors on a variety of cells(including smooth muscle cells and endothelial cells in blood vessels)exerting its biologic effects. These effects include vasodilation,separation of endothelial cells (causing abnormal vascularpermeability), pain and itching. Inhibition of histamine releaseprovides amelioration from many of the adverse effects of inflammation.

“Histamine Receptor Pathway” means that pathway by which cellularreceptors for histamine are activated to bind to histamine, which inturn contributes to the inflammatory condition of tissues or skin.

“Immune challenged” means tissues or skin subjected to environmental,bacterial or viral assaults and where any one or more of the Pathwaysthat contribute to inflammation have been triggered.

“Inflammation” means, when used to describe skin, that the skin has beensubjected to moderate to severe environmental or chemical assault and ismoderately to severely immune challenged. Examples of inflammationinclude sunburn, windburn, acne, insect bites, cuts, burns, rosacea, andthe like. Inflammation typically produces one or more of redness, pain,and heat in the skin.

“Inhibitor” means, when used with a particular Pathway, an ingredient orcombination of ingredients that inhibits the Pathway in whole or inpart. For example, Histamine Pathway Inhibitor means an ingredient orcombination of ingredients that inhibits the Histamine Pathway in wholeor in part.

“Irritation”, when used to describe skin, means that the skin has beenaggravated by environmental assaults or toxins, or application ofproducts containing one or more ingredients to which the skin issensitized or otherwise incompatible. Irritation may result in redness,itchiness, dryness, blemishes, enlarged pores, and so on. Irritated skinmay also exhibit one or more of redness, pain, and heat.

“LO Pathway” means the pathway by which the enzyme lipooxygenase,preferably 5-lipooxygenase, catalyzes the conversion of arachidonic acidto 5-hydroperoxyeicosatetraenoic acid and then to leukotriene A4, whichultimately contributes to inflammation or pain in immune challengedtissue such as skin.

“Liquid” means a composition that is a pourable liquid at roomtemperature.

“Non-volatile” means that the ingredient has a vapor pressure of lessthan about 2 mm. of mercury at 20° C.

“Normal” or “Normalized”, when used to describe skin, means skin that isin its optimum state of natural health. Normalizing skin can includetreating skin to improve irritation or inflammation, or ameliorate orrelieve conditions such as dark under eye circles, or to improve theappearance of wrinkles, lines, uneven pigmentation, sallowness, dryness,laxity, mottled skin, age spots, and the like.

“Pathway”, when used with respect to inflammation, means a cascade ofreactions that occurs when skin or tissue is exposed to immunechallenge, and which ultimately contributes to skin inflammation.

“PDE Pathway” means that pathway by which PDE (phosphodiesterase)including phosphodiesterase-4 (PDE4) cleaves the phosphodiester bondthat may be found in proteins and other molecules present in bacteria,viruses, and other molecules that contribute to skin inflammation. PDE4,in particular, is a member of a family of enzymes that catalyze thedegradation of cAMP to the corresponding 5′-nucleotide monophosphate.PDE4 is abundant and is the major regulator of cAMP metabolism in almostevery pro-inflammatory and immune cell. PDE4 inhibitors exert theiranti-inflammatory effects by inhibiting the breakdown of cAMP (leadingto an increased concentration of cAMP in immune cells) which willultimately lead to a decrease in the production and release ofpro-inflammatory cytokines such as Interleukin 1-β (IL-1β) and TumorNecrosis Factor α (TNFα).

Percentages mentioned herein shall mean percentage by weight unlessotherwise indicated.

“PLA-2 Pathway” means the pathway by which the phospholipase A2 (PLA-2)enzyme hydrolyzes phospholipids to form fatty acid lysophospholipidproducts such as arachidonic acid, which ultimately converts toleukotrienes and prostaglandins, which contribute to the inflammatoryresponse in immune challenged tissue such as skin.

“Plurality” means more than one.

“Semi-solid” means a composition that exists in a cream or paste andwhich is neither pourable or solid at room temperature.

“Solid” means a composition that is a solid at room temperature (e.g.25° C.).

“VEGF Pathway” means the pathway by which VEGF (vascular endothelialgrowth factor) causes angiogensis (the formation of blood vessels) inimmune challenged skin. In addition to inducing angiogenesis, VEGF alsois responsible for increasing vascular leakage which will lead toincreased edema in damaged tissue or skin.

“Volatile” means that the ingredient has a vapor pressure of about 2 mm.of mercury or greater at 20° C.

II. The Methods

The methods of invention include a method for formulating compositionsto treat inflamed or irritated skin, or to treat skin to achievenormalization. In the method of the invention, a plurality of thePathways that contribute to skin inflammation are identified andingredients that inhibit the identified Pathway, either in whole or inpart are selected and formulated into compositions that are then appliedto the skin to treat the skin irritation or inflammation, or tootherwise normalize the skin. Some ingredients have functionality ininhibiting more than one Pathway. In that case that one ingredient maybe incorporated into the composition in an amount sufficient to exert aninhibitory effect on the plurality of Pathways identified.

At this time, the Pathways that contribute to inflammation are believedto be the Adhesion Pathway, the Chemotaxis Pathway, the CollagenasePathway, the COX Pathway, the Elastase Pathway, the Histamine Pathway,the Histamine Receptor Pathway, the LO Pathway, the PDE Pathway, thePLA-2 Pathway, and the VEGF Pathway. However, this invention isconstrued to include pathways that are not identified herein, or may inthe future be identified, or pathways that may be described herein indifferent terms, or as part of larger pathways not fully mentionedherein.

A. Adhesion Pathway

One Pathway that is believed to contribute to inflammation is theAdhesion Pathway. When skin is injured, cells migrate to the area ofinjury as part of the immune response. Such cells adhere to the site ofthe injury to close off broken blood vessels, protect tissues, orotherwise aid in the healing response. Accordingly, ingredients thatinhibit the Adhesion Pathway in whole or in part are selected forformulation in the composition. Such ingredients may be in the form ofbotanical extracts, chemical compounds, polymers, and the like. AdhesionPathway Inhibitors may be present in the formulated compositions inamounts ranging from about 0.0001 to 75%, preferably from about 0.001 to70%, more preferably from about 0.005 to 20%.

One test that is suitable for determining whether a selected ingredientmay inhibit the Adhesion Pathway is based upon the analysis of theadhesion of polymorphonuclear cells (PMN) to human dermal microvasicularcells—one of the things that occurs when leukocytes migrate to a site ofirritation or infection in tissue that has been subject to assault. Thetest is conducted by collecting heparinized peripheral venous blood(about 20-30 ml) from healthy human donors who are requested to refrainfrom caffeine intake for 12 hours prior to the blood drawing. Theheparinized blood from each individual is layered over a densitygradient (Mono-Poly Resolving Media, sold by ICN Pharmaceuticals, CostaMesa, Calif.) and spun at 400×g for 30 minutes. The PMN cell richfraction is removed and the red blood cells lysed with hypotonic saline.The PMN fraction is washed twice with Hank's balanced salt solution(HBSS) and then re-suspended in 5.0 ml HBSS (with ions), which has beensupplemented with 0.4% bovine serum albumin (Sigma Aldrich). Theconcentration of cells is adjusted to 10×10⁶ PMN/ml. Collected PMN aregreater than 95% pure and 98% viable as assessed by the Trypan BlueExclusion Test of Cell Viability, a test well known in the art. Humandermal microvasicular endothelial cells (HDMEC) are obtained from theClonetics Corporation and maintained according to specifications untilconfluent. The PMNs at a concentration of 4×10⁶/ml are mixed 1:1 withthe test material (final concentration of cells=2×10⁶/ml) and incubatedfor 30 minutes with the test material. The appropriate concentration ofmaterial to be tested is determined by conducting standard cytotoxicitytests to identify the highest concentration of test material that causescytotoxicity. After this upper limit has been established successiveserial dilutions of the test material are tested.

After a 30 minute incubation with the test material plus tetradecanoylphorbol acetate (TPA, 5 ng/ml) or, for control, with test materialalone, or with TPA alone or vehicle; the PMN (350,000/well) are added towells of a 96-well microtiter plate in which endothelial cells areseeded at 20,000 cells/well and allowed to reach confluence. Theendothelial cells are activated by pre-incubating with Interleukin-1β(10 U/ml) for 60 minutes at 37° C. in 5% CO₂. After the two cell typeshave been in contact for two hours the supernatant is removed, remainingcells gently rinsed, and 100 ml of 0.25% rose bengal (ICN) stain in PBSis added for 5 minutes at room temperature. Non-adherent cells areremoved by two subsequent washes (Medium 199 with 25 mM HEPES and 10%fetal bovine serum). Stain incorporated into cells is released by theaddition of 200 ml of a 1:1 solution of ethanol and PBS. After 30-45minutes the wells are read in an ELISA reader (Bio-Tek Instruments Inc.Winooski, Vt.) at 570 nm. The level of adherence is given as the meanoptical density reading at an OD570 for wells containing endothelialcells plus PMN minus the mean OD570 of wells containing endothelialcells alone.

While the above test is suitable for ascertaining which selectedingredients inhibit the Adhesion Pathway, other tests, either now knownor hereafter developed may be suitable so long as they accuratelyidentify ingredients that are capable of inhibiting the AdhesionPathway.

Various ingredients have inhibitory activity for the Adhesion Pathway,including but not limited to Algae extract, neem oil limonoids,Asparagus Racemusus extract, Platycodon extract, Chaga Mushroom extract,Emblica Officinalis extract, Criste Marine extract, Lavande Papillonextract, Polygonum Cuspidatum, ginger, Polysea PF (algae extractpurchased from Frutarom), and mixtures of these ingredients.

B. Chemotaxis Pathway

Another Pathway believed to contribute to inflammation is the ChemotaxisPathway. When skin is injured, cells migrate to the area of injury aspart of the immune response. The migration of such cells is calledchemotaxis. Ingredients that inhibit the Chemotaxis Pathway in whole orin part, are selected for formulation in the composition. Theingredients may be in the form of botanical extracts, chemicalcompounds, polymers, and so on. The Chemotaxis Pathway inhibitors may bepresent in the composition ranging from about 0.0001 to 75%, preferablyfrom about 0.0005 to 70%, more preferably from about 0.001 to 20%.

One test that may be used to determine whether a particular ingredientinhibits the Chemotaxis Pathway is one that is based upon the ability ofa test material to inhibit the migration of PMNs toward a knownchemotactic agent. This test is performed by collecting heparinizedperipheral venous blood (20-30 ml) from healthy human donors who arerequested to refrain from caffeine intake for 12 hours prior to theblood drawing. The blood sample is layered over a density gradient(mono-poly resolving media, ICN Pharmaceuticals, Costa Mesa, Calif.) andspun at 400×g for 30 min. The PMN rich fraction is removed and the redblood cells lysed with hypotonic saline. The PMN are washed twice withHank's balanced salt solution (HBSS) and then resuspended in 5.0 ml HBSSwith ions supplemented with 0.4% bovine serum albumin (Sigma). Theconcentration of cells is adjusted to 10×10⁶ PMN/ml. Collected PMNs aregreater than 95% pure and 98% viable as assessed by the Trypan BlueExclusion Assay, which is performed using a Boyden chamber apparatuswith blind well chambers fitted with 5 mm pore size filters (Millipore).The apparatus consists of two vertical chambers separated by a filterthat contains pores of a size chosen such that the holes are largeenough for the cells to actively crawl through them but not so largethat the cells can physically fall through into the lower chamber. PMNare then pre-incubated with test compounds at the indicatedconcentrations. A 200 ml PMN cell suspension is layered on the top ofthe filter, and 100 ml of chemotactic factors are added to the lowercompartment. The chemo-attractant used in the assay is 0.125 nM LTB4.Following incubation at 37° C. for 90 minutes under a humidifiedatmosphere with 5% CO₂, the filters are fixed with propanol and stainedwith haematoxylin and eosin. The PMN chemotactic response is determinedby the distance to the leading front and the number of cells thatmigrated to the front. The distance to the leading front is determinedat 400× magnification by the distance the majority of the cells migratedthrough the filter. The results are expressed as the average number ofcells per high powered field at the leading migratory front (PMN/HPF).

While the above test is suitable for ascertaining which selectedingredients inhibit the Chemotaxis Pathway, other tests, either nowknown or hereafter developed may be suitable so long as they accuratelyidentify ingredients that are capable of inhibiting the ChemotaxisPathway.

Examples of ingredients that inhibit the Chemotaxis Pathway includesulfated polysaccarides such as fucoidan, that may be isolated fromseaweeds such as kombu, limu, moui, bladderwrack, wakame, mozuku,hijiki, and the like; or animal sources such as sea cucumber. Furtherexamples of Chemotaxis Pathway inhibitors include kelp, sea buckthorn,Laminaria Japonica, Fucus Vesiculosis, and the like. Also variousvegetable extracts are excellent inhibitors of the Chemotaxis Pathway,including extracts of onions, potatoes, celery, carrots, turnips,parsley, parsnip, sweet potato, yucca, beets, and the like. Other typesof Chemotaxis Pathway inhibitors include licorice extracts, genestein,extracts from the genus Scutellaria (such a Scutellaria Baicalensis),extracts from the Boswellia genus such as Boswellia Serrata, BoswelliaBhau-dajiana, Boswellia Frereana, Boswellia Papyrfera, SudaneseBoswellia Sacra, and Boswellia Carteri, Commiphora Incisa, CommiphoraMyrrha, Commiphora Abyssinica, Commiphora Erthraea, Commiphora Molmol,and Bursera Microphylla; Nidularium Procerum, sequoia extract,hypoestoxide, Curcuma Longa (turmeric) extract, butyloctyl salicylate,abyssine, plai oil, geranium bourbon oil, jiagolun EX, fucoidan YSK,caffeine, galactoarabinan (sold under the tradename Laracare A200),lion's mane mushroom extract, clerilys, and extracts from MacrycystisPyrifera, reishi mushroom, Pleurotus Ostreatus extract, HypsizygusUlmarius, Cladosiphon Okamuranus Extract, Acalypha Wilkesiana,Acanthopanax Gracilistylus, Allium Sativum, Ananus Comosus, CissampelosSympodialis, Coriolus Versicolor, Echinacea Purpurea, Grifola Frondosa,Harpagophytum Procumbens, Panax Ginseng, Polygala Tenuifolia, PoriaCocos, Silybum Mariamum, Smilax Glabra, Tinospora Cordifolia, UncariaTomentosa, and Withania Somnifera, slime mold, Echinancea, Viscum Album,coffee robusta seed extract, capsaicin, and mixtures thereof.

Suitable inhibitors of the Chemotaxis Pathway may include compounds ormolecules such as TAK-661((2,2-dimethyl-3-[[7-(1-methylethyl)[1,2,4]triazolo[1,5-b]pyridazin-6-yl]oxy]-1-propanesulfonamide),CCRI antagonist, PD172084, CXCR3 antagonist, hexapeptideVal-Gly-Val-Ala-Pro-Gly (VGVAPG) (SEQ ID NO: 1), a recurring sequence inthe elastin molecule ubiquitin, nicotinanalides, Cytochalasin B.

C. Collagenase Pathway

Another Pathway that is believed to contribute to skin inflammation isthe Collagenase Pathway, where the enzyme collagenase is triggered tobreak down the peptide bonds in collagen to destroy the extracellularstructures such as those found in bacteria and viruses that, when incontact with skin or tissues cause injury or immune challenge.Collagenase Pathway Inhibitors will inhibit the activity of thecollagenase enzyme so that it will not destroy collagen, for example,the collagen like that found in the cellular or extracellular structuresof bacteria or lymphocytes at the site of injury. The CollagenasePathway Inhibitors may be present in amounts ranging from about 0.0001to 75%, preferably from about 0.0005 to 70%, more preferably from about0.001 to 20%.

A simple test that can determine whether a particular ingredientinhibits the Collagenase Pathway is a fluorescent microtiter assay basedupon the principle that matrix metalloproteinase-1 (MMP-1), interstitialcollagenase, or fibroblast collagenase can cleave the quenchedfluorescent peptide OmniMMP™ (Mca-PLGLDpaAR from Biomol) at the Gly-Leubond. Upon enzymatic cleavage the fluorescent tag is released and thefluorescence increases as the enzymatic reaction progresses. Thepresence of an MMP-1 inhibitor will cause a reduction in fluorescence.The MMP-1 is obtained from R & D Systems as a proenzyme that must beactivated with p-aminophenylmercuric acetate (APMA).

To perform this assay, the following solutions are prepared: AssayBuffer (50 mM Tris, 10 mM CaCl₂, 150 mM NaCl, 0.05% Brij, pH 7.5), 400μM OmniMMP peptide in DMSO, 0.7 μMN-isobutyl-N-(4-methoxyphenylsulfonyl)glycyl hydroxamic acid (NNGH,reference inhibitor from Biomol) in DMSO and 20 mM APMA in DMSO. 100μg/ml of MMP-1 is activated with APMA at a final concentration of 1 mM(for 1 hour at 37° C. in the dark). After activation, the MMP-1 isdiluted to 0.88 μg/ml. The activated MMP-1 is tested at a finalconcentration of 0.18 μg/ml in the wells of a 96 well plate. Potentialinhibitors are tested at final concentration of 200, 100, 50 and 25μg/ml. The reaction is carried out in a 96 well plate by addingappropriate volumes of activated MMP-1, reference inhibitor or potentialinhibitors and incubating in the dark for 1 hour at room temperature.After the 1 hour incubation, the OmniMMp peptide is added to each wellto a final concentration of 4 μM. The fluorescence (320_(ex)/400_(em))is then monitored in a fluorescent plate reader for 1 hour. Thefluorescence readings for each sample are plotted versus time and theinitial reaction velocity is calculated from the initial slope of thefluorescence versus time for each inhibitor concentration. The initialreaction velocity is plotted as a function of the end concentration ofthe potential inhibitor and the IC₅₀ is then calculated. The IC₅₀corresponds to the concentration of inhibitor that results in a 50%reduction of the initial reaction velocity in the absence of theinhibitor.

While the above test is suitable for ascertaining which selectedingredients inhibit the Collagenase Pathway, other tests, either nowknown or hereafter developed may be suitable so long as they accuratelyidentify ingredients that are capable of inhibiting the CollagenasePathway.

A variety of ingredients are known to be Collagenase Pathway Inhibitors,including but not limited to those from the Siegesbeckia genus such asSiegesbeckia Orientalis; the Doliocarpus genus such as DoliocarpusVerruculosus; the Kaempferia genus such as Kaempferia Galanga rootextract; the Camilla genus such as Camilla Sinensis; the Sauropus genussuch as Sauropus Androgynus; the Tetracapidium genus such asTetracapidium Conophorum; glucosamine, N-acetyl glucoseamine,chondroitan sulfate, Pinus Pinaster (pine bark) extract, lysine, VitisVinefera (grape) seed extract, retinoids such as retinyl palmitate,retinol, retinoic acid; extracts from the Pluchea genus such as PlucheaIndica (Compositae); the Viola genus such as Viola Hondoensis; cocoabean; the Triphala genus such as Triphala Chebula, anthocyanins,epigallocatechingallate, epicatechingallate, luteolin, Citri Reticulataepeel extract, winter begonia extract; the Tepescohuite genus, such asTepescohuite spray dried extract; from the Mimosa genus such as MimosaPudica extract, picolinic acid, climmp-19, Silymarin extract, Eucommiaextract, amentoflavone; from the Menyanthes genus such as MenyanthesTrifoliate extract; or mixtures thereof.

D. COX Pathway

In the COX Pathway the cyclooxygenase (COX) enzyme (including but notlimited to cyclooxygenase-2 or COX-2) converts arachidonic acid and/orother fatty acids to prostaglandin or prostanoids. It is theseprostaglandins or prostanoids that ultimately contribute to inflammationby causing pain near the sites of the immune challenge or damage. COXPathway Inhibitors will block the conversion of arachidonic or otherfatty acids to prostaglandin or prostanoids in whole or in part. The COXPathway Inhibitors may be present in amounts ranging from about 0.0001to 75%, preferably from about 0.0005 to 70%, more preferably from about0.001 to 20%.

COX-2 is responsible for the biosynthesis of prostaglandins under acuteinflammatory conditions. COX-2 is believed to be the target enzyme forthe anti-inflammatory activity of nonsteroidal anti-inflammatory drugs.The COX Inhibitor Screening Assay Kit from Cayman Chemical (560131)directly measures PGF_(2a) produced by SnCl₂ reduction of COX-derivedPGH₂. The prostanoid product is quantified via enzyme immunoassay (EIA)using a broadly specific antibody that binds to all the majorprostaglandin compounds. The COX Inhibitor Screening Assay was performedas outlined in the protocol supplied by the manufacturer and the resultscalculated from the standard curve.

While the above test is suitable for ascertaining which selectedingredients inhibit the COX Pathway, other tests, either now known orhereafter developed may be suitable so long as they accurately identifyingredients that are capable of inhibiting the COX Pathway.

A variety of ingredients are COX Pathway inhibitors, including but notlimited to extracts of plants from the Acacia genus, Calluna Vulgaris,Rosa Canina fruit extract, nettle leaf extract, Polyporus Umbellatus,Chamomilla Recutita (Matricaria) flower oil, Rusperin C® (a mixture ofButcher's Broom extract and heperidin methyl chalcone), resveratrol,HOP's beta acids, and mixtures thereof.

E. Elastase Pathway

In the Elastase Pathway, in response to immune challenge or tissuedamage the enzyme elastase is released to degrade proteins includingelastin that are found in bacteria or invading cells. When the ElastasePathway is triggered the cascade of reactions also contributes toinflammation or pain in immune challenged tissue such as skin. TheElastase Pathway Inhibitors may be present in amounts ranging from0.0001 to 75%, preferably from about 0.0005 to 70%, more preferably fromabout 0.001 to 20%.

A simple test that can be performed to determine whether an ingredientinhibits the Elastase Pathway is performed by using a synthetic elastasesubstrate (Meo-suc-ala-ala-pro-val-pNa peptide from Sigma) and dilutingto 200 μM in Dulbecco's PBS (no Calcium or Magnesium) containing 5%dimethylsulfoxide (DMSO) and 50 μl are added to a 96 well plate.Potential inhibitors are diluted in Dulbecco's PBS (D-PBS) containing10% DMSO and 5 μl are added to the plate and allowed to equilibrate for5 minutes at room temperature. Potential inhibitors are typically testedat final concentrations of 1, 10, 100 and 1000 peril for powderedsamples and at 0.001, 0.01, 0.1 and 1% (v/v) for liquid samples. Humanleukocyte elastase (Sigma) is diluted to 0.005 mg/ml with D-PBS/5% DMSOand 50 μl are added to the wells of the plate. Kinetic readings of theoptical density at 405 nm are monitored for 10 minutes and the Vmax isdetermined. The EC50 for each inhibitor is then calculated. While thistest may be used to identify ingredients that inhibit the ElastasePathway, other tests may be suitable and this invention is not limitedto one specific test. Any other test that is known in the art either nowor hereafter and which accurately predicts the Elastase Inhibitionactivity of an ingredient may also be used to identify and selectsuitable ingredients that inhibit the Elastase Pathway.

A number of ingredients are suitable inhibitors of the Elastase Pathwayincluding Boswellia Serratia extract, winter begonia extract, oleanolicacid, ursolic acid, phytocohesin, Pygeum Africanum extract, PadinaPavonica extract, CP7 PC 16, Actina Boswellia extract, ligustrum,dipalmitoyl hydroxyproline (sold under the tradename Sepilift DPHP bySeppic), Soft Pygeurm extract, chaga mushroom, 7-DHC(7-dehydrocholesterol), white birch extract, polyphenon E, jojobaprotein isolate, red raspberry powder, heather extract, hesperitin,hibiscin, Preregen® (mixture of soybean protein and oxido reductases),grapeseed extract, Rusperin C® (a mixture of butcher's broom extract andheperidin methyl chalcone), hesperidin, caffeine, Pronalen® (a proteinhydrolysate obtained from extracted organic germinated wheat seeds)hesperitin, Elhibin® (glycine soja protein), jojoba oil, PhytessenceOlive® (a mixture of butylene glycol, water and Olea Europaea fruitextract).

F. Histamine Pathway

The Histamine Pathway is the pathway where the amino acid histidine isdecarboxylated to form histamine—a reaction that occurs in response toimmune challenge or other injury to tissue or skin. The HistaminePathway Inhibitors may be present in amounts ranging from about 0.0001to 75%, preferably from about 0.0005 to 70%, more preferably from about0.001 to 20%.

A test that may be conducted to determine whether an ingredient inhibitsthe Histamine Pathway may be performed by first growing cells from therat basophil leukemia (RBL) cell line in Dulbecco's Modification ofEagle Medium (DMEM) with 10% heat activated fetal calf serum (FCS) andseeding in 24 well plates at 2.5×10⁵ cells/well. The cells are grownovernight and treated the next day. Reagents are prepared in DMSO withcomplete solubilization, specifically: epigallocatechin gallate (EGCG)(100 mM); chrysin (10 mM); apigenin (10 mM); phloridizin (10 mM);curcumin (orange) (10 mM); and gallic acid (10 mM). Chrysin is used as apositive control. Prior to treating the RBL cells, the overnight culturemedia is removed and the cells washed with phosphate buffered saline(PBS) and equilibrated with PIPES buffer, pH 7.2. (PIPES buffer contains100 mM NaCl, 5 mM KCl, 0.4 mM MgCl₂, 1 mM CaCl₂ and 5.6 mM D-glucose.PIPES buffer is known to reduce spontaneous release of histamine).Potential inhibitors of histamine release are added directly to thePIPES buffer (37° C.) and incubated for 30 minutes. Cells were exposedto 100 mM, 10 mM, 1 mM and 0.1 mM doses of the inhibitors. Histaminerelease was induced by the calcium-ionophore, A23187 (2 mM final) (SigmaC7522). The supernatant was harvested after 30 minutes of exposure tothe ionophore and assayed using a Histamine ELISA kit from IBL(distributed by Research Diagnostics). The Histamine ELISA was performedas outlined in the protocol supplied by the manufacturer and the resultscalculated from the standard curve.

While the above test is suitable for ascertaining which selectedingredients inhibit the Histamine Pathway, other tests, either now knownor hereafter developed may be suitable so long as they accuratelyidentify ingredients that are capable of inhibiting the HistaminePathway.

Ingredients that are known to inhibit the Histamine Pathway includebotanicals such as apigenin which is a flavone that may be extractedfrom celery, parsley, or citrus fruits such as grapefruit peel extract;amentoflavone (which may be isolated from Selaginella Tamariscina;luteolin, a flavinoid; phloretin, or2′,4′,6′,4-Tetrahydroxydihydrochalcone; grapeseed extract, RosmarinusOfficinalis extract, or mixtures of such materials.

G. Histamine Receptor Pathway

The Histamine Receptor Pathway refers to a pathway by which cellularreceptors for histamine are activated to bind to histamine, which inturn contributes to the inflammatory condition of tissues or skin. TheHistamine Receptor Pathway Inhibitors may be present in amounts rangingfrom 0.0001 to 75%, preferably from about 0.0005 to 70%, more preferablyfrom about 0.001 to 20%.

A test that may be conducted to determine whether an ingredient inhibitsthe Histamine Receptor Pathway is performed by radio ligand bindingassay. Cellular membranes from recombinant Chinese hamster ovary celllines are transfected with human H1 receptor cells. Test material atconcentrations ranging from 1000 μM to 1 μM are pre-incubated with thecellular membranes. The reaction is initiated by addition ofradioactively labeled guanosine 5′-tri phosphate that is unable to bemetabolized [³⁵S]GTPγS and incubated for an additional 30 minutes at 30°C. When histamine binds to the H1 receptor on the cell membranes, aconformational change occurs in the alpha G protein subunit that is alsopresent on the cell membranes in this assay allowing the [³⁵S]GTPγS tobind to the G protein subunit. It is the presence of this boundradioactive ligand that is monitored. If the test compound in thepresence of histamine reduces [35S]GTPgS binding by the alpha G proteinby 50 percent or more, this indicates receptor antagonist activity.

While the above test is suitable for ascertaining which selectedingredients inhibit the Histamine Receptor Pathway, other tests, eithernow known or hereafter developed may be suitable so long as theyaccurately identify ingredients that are capable of inhibiting theHistamine Receptor Pathway.

Suitable Histamine Receptor Pathway Inhibitors include Xanomax® (a highpotency extract of Mangosteen), Japanese Butterbur, Garcinia MangostanaPeel Extract (sold under the tradename Xanomax 40% by Amax Nutrasource,Inc.), and mixtures thereof.

H. LO Pathway

The LO Pathway means the pathway by which the enzyme lipooxygenase,preferably 5-lipooxygenase, catalyzes the conversion of arachidonic acidto 5-hydroperoxyeicosatetraenoic acid and then to leukotriene A4, whichultimately contributes to inflammation or pain in immune challengedtissue such as skin. The LO Pathway Inhibitors may be present in amountsranging from about 0.0001 to 75%, preferably from about 0.0005 to 70%,more preferably from about 0.001 to 20%.

A simple test that can be used to determine whether an ingredient isable to inhibit the LO Pathway is performed by slightly modifying theprocedure in a kit—The Lipoxygenase Inhibitor Screening Assay Kit fromCayman Chemical (760700)—but where the 15-Lipooxygenase that is found inthe kit is substituted with 5-LO (also purchased from Cayman Chemical,60401). The 5-LO is diluted to 225 U/ml in 0.1M Tris-HCl (pH 7.4) and 90μl (20 U) are added to each well of a 96 well plate. Caffeic acid isused as a control and added to the well at a final concentration of 300μg/ml. The test samples are usually tested at final concentrations of 1,10, 100 and 1000 μg/ml. Upon addition of the enzyme and test sample, thecontents of the wells are mixed and incubated for 5 minutes. Theenzymatic reaction is initiated with the addition of linoleic acid(substrate) at a final concentration of 100 μM in the wells. The plateis then placed on an orbital shaker for 5 minutes. After the 5 minutereaction time, a chromogen is then added to each well and allowed toreact for 10 minutes. The chromogen reacts with the hydro-peroxidesproduced as a result of the lipoxygenation reaction and also acts tostop the reaction. The resulting “color” is read on the plate reader at500 nm. The absorbance at 500 nm is proportional to the level of 5-LOactivity. The percent inhibition is then calculated based on theabsorbance in the presence and absence of the inhibitor.

While the above test is suitable for ascertaining which selectedingredients inhibit the 5-LO Pathway, other tests, either now known orhereafter developed may be suitable so long as they accurately identifyingredients that are capable of inhibiting the 5-LO Pathway.

Suitable LO Pathway Inhibitors include Haplophyllum hispanicum Spach,Scutellaria Rivularis extracts and its active components, alphaketoboswellic acid, Zileuton®(1-(1-benzothiophen-2-ylethyl)-1-hydroxy-urea), Centaurium extract,nordihydroguaiaretic acid, ginger oil, resveratrol, Polygonum Cuspidatumextract, cedar himalaya extract, tetrahydrocurcuminoids, Nigella Sativaessential oil, copaiba balsam, Australian sandalwood, Rhodiola Rosea,frankincense, blue cypress oil, blue chamomile oil, anti-inflammatoryoil blend, vetiver mada, bulgarian rose oil, Helichrysum oil, rosmarinicacid, resveratrol triphosphate, noni leaf extract, and mixtures thereof.

I. PDE Pathway

The PDE Pathway means that pathway by which PDE (phosphodiesterase)including phosphodiesterase-4 cleaves the phosphodiester bond that maybe found in proteins and other molecules present in bacteria, viruses,and other molecules that contribute to skin inflammation.

A test for determining whether an ingredient inhibits the PDE Pathwaymay be performed using a radionuclide assay using [3H] cAMP as asubstrate. The test procedure utilizes purified cAMP dependentphosphodiesterase (PDE4). All test materials are suspended or dissolvedin 1% DMSO. The test materials (at concentrations ranging from 0.001 to1000 μg/ml) are incubated with the purified PDE4 enzyme for 20 minutesbefore determining the amount of [³H] adenosine generated. Uponincubation, the PDE4 enzyme will convert the [3H] cAMP to [³H] adenosinewhich is then measured via scintillation counter. IBMX(isobutylmethylxanthine) was used as the positive control inhibitor (at4.35 μg/ml).

While the above test is suitable for ascertaining which selectedingredients inhibit the PDE Pathway, other tests, either now known orhereafter developed may be suitable so long as they accurately identifyingredients that are capable of inhibiting the PDE Pathway.

Examples of PDE Pathway Inhibitors include nordihydroguaiaretic acid,emodin (an extract from Rheum Emodi or rhubarb), 18-B-glycerrhetinicacid, caffeine, wild yarn powder, Anemarrhena asphodeloides or Zhi Muextract, Eucomia extract, Uncaria Tomentosa (also referred to as C-med100), or mixtures thereof.

J. PLA Pathway

The term PLA Pathway means the pathway by which PLA-2 (the phospholipaseA2 enzyme) hydrolyzes phospholipids to form fatty acid lysophospholipidproducts such as arachidonic acid, which ultimately converts toleukotrienes and prostaglandins and contributes to the inflammatoryresponse in immune challenged tissue such as skin. PLA PathwayInhibitors may be present from about 0.0001 to 75%, preferably fromabout 0.0005 to 70%, more preferably from about 0.001 to 20%.

A test that determines whether an ingredient has PLA Pathway inhibitingproperties may be conducted by preparing a stock solution of substrate,2-(6-(7-nitrobenz-2-oxa-1,3-diaazol-4-yl)amino)-hexanoyl-1-hexadecanoyl-sn-glycero-3-phosphocholine(NBDC6-HPC sold by Molecular Probes) (1 mM in EtOH) diluted 1:100 inD-PBS. The final concentration of substrate is 0.001 mM as the assaydilutes all components 10 fold. The positive control, thioetheramide(Cayman, 62750), is tested at a final concentration of 5 μM. The samplesto be tested are tested at a final concentration of 0.001%, 0.01%, 0.1%and 1% [v/v] or at 1, 10, 100 and 1000 μg/ml in D-PBS. The PLA2 enzymeused is the secretory PLA2 human enzyme Type V (Cayman 10004913). Theenzyme final concentration tested is a 1:1000 dilution of the suppliedvial. The reaction proceeded in 200 μl total solution initiated byaddition of enzyme. Fluorescence is read immediately and subsequentlyeach minute for a total of 8 minutes. (Excitation 470 nm Emission 540nm). The fluorescence readings for each sample are plotted versus timeand the initial reaction velocity is calculated from the initial slopeof the fluorescence versus time for each inhibitor concentration. Theinitial reaction velocity is plotted as a function of the endconcentration of the potential inhibitor and the IC₅₀ is thencalculated. The IC₅₀ corresponds to the concentration of inhibitor thatresults in a 50% reduction of the initial reaction velocity in theabsence of the inhibitor.

While the above test is suitable for ascertaining which selectedingredients inhibit the PLA Pathway, other tests, either now known orhereafter developed may be suitable so long as they accurately identifyingredients that are capable of inhibiting the PLA Pathway.

Ingredients that are suitable for inhibiting the PLA Pathway includebotanicals such as Lyngbya extract, grapeseed extract, amentoflavone,Licochalcone, polypore, Viapure Poria extract, Polyporus Umbellatus,Avocado extract, Camelia Sinensis extract, Chrysanthellum Indicum,Tridentate marginata extract (also referred to as tridentatol C),pomegranate extract, ellagic acid, paeoniflorin PR-3 (an extract ofPaeonia Albiflora Pall) hesperitin, green tea polyphenols, Gorgonianextract, and mixtures thereof.

K. VEGF Pathway

The VEGF Pathway means the pathway by which VEGF (vascular endothelialgrowth factor) causes angiogensis (the formation of blood vessels) inimmune challenged or damaged skin or tissue. The VEGF Pathway Inhibitorsmay be present in amounts ranging from 0.0001 to 75%, preferably fromabout 0.0005 to 70%, more preferably from about 0.001 to 20%.

A test that is suitable for determining whether a particular ingredientinhibits the VEGF Pathway is based upon the analysis of the ability ofthe test material to inhibit the synthesis and release of VEGF fromNormal Human Epidermal Keratinocytes that have been stimulated witheither tumor necrosis factor a (TNFa), or UVA or UVB rays.

Normal Human Epidermal Keratinocytes (Cascade Biologics) are seeded andgrown to subconfluence in 6 well plates. Upon reaching subconfluence,the EGF and Bovine Pituitary Extract (BPE) are removed from the mediaand the test materials tested at final concentrations of 0.0001, 0.001,0.01, 0.1 and 1 mg/ml for powdered samples or at 0.001%, 0.01%, 0.1% or1% (v/v) for liquid samples. After incubating for 48 hours, the cellsare stimulated with either TNFa (50 ng/ml from R&D Systems), UVA (10J/m², F20T12-BLB bulbs) or UVB (20 mJ/cm², FS40 bulbs) and incubated foran additional 24 hours in the presence of the test material. At theconclusion of the 24 hour incubation, supernatants are harvested andVEGF levels are measured via an ELISA technique (R&D Systems). The VEGFELISA was performed as outlined in the protocol supplied by themanufacturer and the results calculated from the standard curve.

While the above test is suitable for ascertaining which selectedingredients inhibit the VEGF Pathway, other tests, either now known orhereafter developed may be suitable so long as they accurately identifyingredients that are capable of inhibiting the VEGF Pathway.

Suitable VEGF Pathway Inhibitors include extracts from the Saussureagenus such as Saussurea Costus extract, Saussurea Lappa, Sesquiterpenelactones, magnolia extract, Biobenefity® (a mixture of butylene glycol,water, and Cynara Scolymus (Artichoke) Leaf Extract), hypoestoxide (HE);and Magnolia Officianalis Bark extract, Echineacea Pallida extract, andmixtures thereof.

In the method of the invention a plurality of Pathways are identifiedand ingredients that have an inhibitory effect on the Pathwaysidentified are selected by performing the tests mentioned herein orsimilar tests that predict the efficacy of the selected material ininhibiting the pathway of interest. The active materials are thenincorporated into a composition suitable for topical application. Two,three, four, five, six, seven, eight, nine, ten, or all eleven Pathwaysmay be identified and the corresponding inhibitory ingredients for eachof the Pathways identified are formulated into the topical composition.

For example, it is believed that dark under eye circles, one feature ofskin that is not normalized, may be caused by inflammatory reactionsinvolving one or more of the Pathways mentioned herein. In that case,the Pathways that contribute to the type of inflammation or irritationthat produces dark under eye circles are identified, then the particularingredients that inhibit the Pathways identified are selected. Theselected ingredients are formulated into a topical composition that canbe applied to the affected area one or more tunes per day to treat thecondition.

In another example, skin that has been sunburned is red, painful, andwarm. A Plurality of the Pathways are identified, ingredients areselected that inhibit the identified Pathways, and the ingredients areformulated into a topical composition for use in treating the sunburnedskin.

In yet another example, certain irritated conditions contribute to agedskin. For example, sallow pigmentation or age spots may be due in partto inflammatory conditions. In this case the Pathways that contribute tothe sallow pigmentation or age spots are identified, ingredients areselected that inhibit the Pathways identified, and those ingredients areformulated into a topical composition for application to treat thesallow pigmentation or age spots.

The invention also comprises a method for treating irritated or inflamedskin, or skin that is no longer normalized, by identifying a pluralityof Pathways that contribute to inflammation, selecting ingredients thatinhibit the Pathways identified, and formulating those ingredients intoa topical composition for application to skin to treat the condition.

The topical compositions may be in the form of creams, lotions, sprays,mousses, toilers, soaps, color cosmetic products, and so on. They may beapplied once, twice, or more times per day. They may be applied inregimens, or as part of a regimen. For example, in the morning the usermay cleanse and tone the skin and apply the composition preparedaccording to the invention. Then in the evening prior to retiring theuser may again cleanse and tone the skin and apply the composition as anight cream. The Pathway inhibitory ingredients may be found in allsteps of the regimen or only one. For example, the Pathway inhibitoryingredients may be found in the cleanser, toner, and skin cream orlotion, Alternatively, the Pathway inhibitory ingredients may be foundonly in the toner and skin cream, or skin cream alone. The Pathwayinhibitory ingredients may also be formulated into color cosmetics suchas foundations, blush, concealer, eye shadow, lipstick, and so on.

III. The Compositions

The compositions used in the methods of the invention may comprise avariety of other ingredients. The compositions may be found in theanhydrous, emulsion, gel, solution, or suspension form. If present inthe solution or gel form, from about 0.01-99%, preferably from about0.5-95%, more preferably from about 1-90% by weight of the totalcomposition of water may be present. If present in the emulsion form,water-in-oil or oil-in-water emulsions may be appropriate, in which casein addition to the amounts of water already mentioned, the compositionsmay contain from about 0.01-98%, preferably from about 0.1-95%, morepreferably from about 0.5-90% by weight of the total composition of oil.The composition may contain a variety of other ingredients including butnot limited to those set forth herein. If present in the solution or gelform, the composition may comprise from about 0.01-99% water and otheroptional ingredients. If present in the anhydrous form, the compositionmay contain waxes, oils, or humectants in the amounts set forth herein.

A. Volatile Oils

1. Volatile Silicones

Suitable volatile oils that may be used in the compositions of theinvention generally have a viscosity ranging from about 0.5 to 5centistokes 25° C. and include linear silicones, cyclic silicones,branched silicones, paraffinic hydrocarbons, or mixtures thereof.

Cyclic silicones are of the general formula:

where n=3-6.

Linear volatile silicones in accordance with the invention have thegeneral formula:(CH₃)₁Si—O[Si(CH₃)₁—O]_(n)—SiCH₃)₃where n=0, 1, 2, 3, 4, or 5, preferably 0, 1, 2, 3, or 4.

Branched volatile silicones are generally of the formula:

wherein R is C₁₋₄ alkyl, preferably methyl.

Linear and cyclic volatile silicones are available from variouscommercial sources including Dow Corning Corporation and GeneralElectric. The Dow Corning volatile silicones are sold under thetradenames Dow Corning 244, 245, 344, and 200 fluids. These fluidscomprise octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane,dodecamethylcyclohexasiloxane and the like. Also suitable are linearvolatile silicones such as hexamethyldisiloxane (viscosity 0.65centistokes (abbreviated cst)), octamethyltrisiloxane (1.0 cst),decamethyltetrasiloxane (1.5 cst), dodecamethylpentasiloxane (2 cst) andmixtures thereof.

Suitable branched volatile silicones include methyl trimethicone, ethyltrimethicone, propyl trimethicone, butyl trimethicone and the like.Methyl trimethicone may be purchased from Shin-Etsu Silicones and hasthe trade name TMF 1.5, having the viscosity of 1.5 centistokes at 25°C.

2. Volatile Paraffinic Hydrocarbons

Also suitable as the volatile oils are various straight or branchedchain paraffinic hydrocarbons having 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, or 20 carbon atoms, more preferably 8 to 16 carbonatoms. Suitable hydrocarbons include pentane, hexane, heptane, decane,dodecane, tetradecane, tridecane, and C₈₋₂₀ isoparaffins as disclosed inU.S. Pat. Nos. 3,439,088 and 3,818,105, both of which are herebyincorporated by reference in their entireties for all purposes.

Preferred volatile paraffinic hydrocarbons have a molecular weight of70-225, preferably 160 to 190 and a boiling point range of 30 to 320,preferably 60 to 260° C., and a viscosity of less than about 10 cst. at25° C. Such paraffinic hydrocarbons are available from EXXON under theISOPARS trademark, and from the Permethyl Corporation. Suitable C₁₂isoparaffins are manufactured by Permethyl Corporation under thetradename Permethyl 99A. Various C₁₆ isoparaffins commerciallyavailable, such as isohexadecane (having the tradename Permethyl R), arealso suitable.

B. Non-Volatile Oils

A variety of nonvolatile oils are also suitable for use in the cosmeticcompositions of the invention. The nonvolatile oils generally have aviscosity of greater than about 5 to 10 centistokes at 25° C., and mayrange in viscosity up to about 1,000,000 centipoise at 25° C.Preferably, the nonvolatile oils are liquid. Further examples ofnonvolatile oils include, but are not limited to:

1. Esters

Suitable esters are mono-, di-, and triesters. The composition maycomprise one or more esters selected from the group, or mixturesthereof.

(a) Monoesters

Monoesters are defined as esters formed by the reaction of amonocarboxylic acid having the formula R—COOH, wherein R is a straightor branched chain saturated or unsaturated alkyl having 2 to 45 carbonatoms, or phenyl; and an alcohol having the formula R—OH wherein R is astraight or branched chain saturated or unsaturated alkyl having 2-30carbon atoms, or phenyl. Both the alcohol and the acid may besubstituted with one or more hydroxyl groups. Either one or both of theacid or alcohol may be a “fatty” acid or alcohol, and may have fromabout 6 to 30 carbon atoms, more preferably 12, 14, 16, 18, or 22 carbonatoms in straight or branched chain, saturated or unsaturated form.Examples of monoester oils that may be used in the compositions of theinvention include hexyl laurate, butyl isostearate, hexadecylisostearate, cetyl palmitate, isostearyl neopentanoate, stearylheptanoate, isostearyl isononanoate, steary lactate, stearyl octanoate,stearyl stearate, isononyl isononanoate, and so on.

(b). Diesters

Suitable diesters are the reaction product of a dicarboxylic acid and analiphatic or aromatic alcohol or an aliphatic or aromatic alcohol havingat least two substituted hydroxyl groups and a monocarboxylic acid. Thedicarboxylic acid may contain from 2 to 30 carbon atoms, and may be inthe straight or branched chain, saturated or unsaturated form. Thedicarboxylic acid may be substituted with one or more hydroxyl groups.The aliphatic or aromatic alcohol may also contain 2 to 30 carbon atoms,and may be in the straight or branched chain, saturated, or unsaturatedform. Preferably, one or more of the acid or alcohol is a fatty acid oralcohol, i.e. contains 12-22 carbon atoms. The dicarboxylic acid mayalso be an alpha hydroxy acid. The ester may be in the dimer or trimerform. Examples of diester oils that may be used in the compositions ofthe invention include diisotearyl malate, neopentyl glycol dioctanoate,dibutyl sebacate, dicetearyl dimer dilinoleate, dicetyl adipate,diisocetyl adipate, dilsononyl adipate, diisostearyl dimer dilinoleate,diisostearyl fumarate, diisostearyl malate, dioctyl malate, and so on.

(c). Triesters

Suitable triesters comprise the reaction product of a tricarboxylic acidand an aliphatic or aromatic alcohol or alternatively the reactionproduct of an aliphatic or aromatic alcohol having three or moresubstituted hydroxyl groups with a monocarboxylic acid. As with themono- and diesters mentioned above, the acid and alcohol contain 2 to 30carbon atoms, and may be saturated or unsaturated, straight or branchedchain, and may be substituted with one or more hydroxyl groups.Preferably, one or more of the acid or alcohol is a fatty acid oralcohol containing 12 to 22 carbon atoms. Examples of triesters includeesters of arachidonic, citric, or behenic acids, such as triarachidin,tributyl citrate, triisostearyl citrate, tri C₁₂₋₁₃ alkyl citrate,tricaprylin, tricaprylyl citrate, tridecyl behenate, trioctyldodecylcitrate, tridecyl behenate; or tridecyl cocoate, tridecyl isononanoate,and so on.

Esters suitable for use in the composition are further described onpages 2679-2688 of Volume 3 of the C.T.F.A. Cosmetic IngredientDictionary and Handbook, Eleventh Edition, 2006, which is herebyincorporated by reference in its entirety.

2. Hydrocarbon Oils

It may be desirable to incorporate one or more nonvolatile hydrocarbonoils into the composition. Suitable nonvolatile hydrocarbon oils includeparaffinic hydrocarbons and olefins, preferably those having greaterthan about 20 carbon atoms. Examples of such hydrocarbon oils includeC₂₄₋₂₈ olefins, C₃₀₋₄₅ olefins, C₂₀₋₄₀ isoparaffins, hydrogenatedpolyisobutene, polyisobutene, polydecene, hydrogenated polydecene,mineral oil, pentahydrosqualene, squalene, squalane, and mixturesthereof. In one preferred embodiment such hydrocarbons have a molecularweight ranging from about 300 to 1000 Daltons.

3. Glyceryl Esters of Fatty Acids

Synthetic or naturally occurring glyceryl esters of fatty acids, ortriglycerides, are also suitable for use in the compositions. Bothvegetable and animal sources may be used. Examples of such oils includecastor oil, lanolin oil, C₁₀₋₁₈ triglycerides,caprylic/capric/triglycerides, sweet almond oil, apricot kernel oil,sesame oil, camelina sativa oil, tamanu seed oil, coconut oil, corn oil,cottonseed oil, linseed oil, ink oil, olive oil, palm oil, illipebutter, rapeseed oil, soybean oil, grapeseed oil, sunflower seed oil,walnut oil, and the like.

Also suitable are synthetic or semi-synthetic glyceryl esters, such asfatty acid mono-, di-, and triglycerides which are natural fats or oilsthat have been modified, for example, mono-, di- or triesters of polyolssuch as glycerin. In an example, a fatty (C₁₂₋₂₂) carboxylic acid isreacted with one or more repeating glyceryl groups. glyceryl stearate,diglyceryl diiosostearate, polyglyceryl-3 isostearate, polyglyceryl-4isostearate, polyglyceryl-6 ricinoleate, glyceryl dioleate, glyceryldiisotearate, glyceryl tetraisostearate, glyceryl trioctanoate,diglyceryl distearate, glyceryl linoleate, glyceryl myristate, glycerylisostearate, PEG castor oils, PEG glyceryl oleates, PEG glycerylstearates, PEG glyceryl tallowates, and so on.

4. Nonvolatile Silicones

Nonvolatile silicone oils, both water soluble and water insoluble, arealso suitable for use in the composition. Such silicones preferably havea viscosity ranging from about 10 to 800,000 cst, preferably 20 to200,000 cst at 25° C. Suitable water insoluble silicones include aminefunctional silicones such as amodimethicone; phenyl substitutedsilicones such as bisphenylhexamethicone, trimethylsiloxyphenyldimethicone, phenyl trimethicone, or polyphenylmethylsiloxane;dimethicone, dimethicone substituted with C₂₋₃₀ alkyl groups such cetyldimethicone.

Nonvolatile silicones may have the following general formula:

wherein R and R′ are each independently C₁₋₃₀ straight or branchedchain, saturated or unsaturated alkyl, phenyl or aryl, trialkylsiloxy,and x and y are each independently 0-1,000,000; with the proviso thatthere is at least one of either x or y, and A is alkyl siloxy endcapunit. Preferred is where A is a methyl siloxy endcap unit; in particulartrimethylsiloxy, and R and R′ are each independently a C₁₋₃₀ straight orbranched chain alkyl, phenyl, or trimethylsiloxy, more preferably aC₁₋₂₂ alkyl, phenyl, or trimethylsiloxy, most preferably methyl, phenyl,or trimethylsiloxy, and resulting silicone is dimethicone, phenyldimethicone, diphenyl dimethicone, phenyl trimethicone, ortrimethylsiloxyphenyl dimethicone. Other examples include alkyldimethicones such as cetyl dimethicone, and the like wherein at leastone R is a fatty alkyl (C₁₂, C₁₄, C₁₆, C₁₈, C₂₀, or C₂₂), and the otherR is methyl, and A is a trimethylsiloxy endcap unit, provided such alkyldimethicone is a pourable liquid at room temperature. Phenyltrimethicone can be purchased from Dow Corning Corporation under thetradename 556 Fluid. Trimethylsiloxyphenyl dimethicone can be purchasedfrom Wacker-Chemie under the tradename PDM-1000. Cetyl dimethicone, alsoreferred to as a liquid silicone wax, may be purchased from Dow Corningas Fluid 2502, or from DeGussa Care & Surface Specialties under thetradenames Abil Wax 9801, or 9814.

C. Surfactants

The composition of the invention may contain one or more surfactants.The surfactants may be silicone or organic surfactants.

1. Silicone Surfactants

Suitable silicone surfactants include polyorganosiloxane polymers thathave amphiphilic properties, for example contain both hydrophilicradicals and lipophilic radicals. These silicone surfactants may beliquids or solids at room temperature and include, but are not limitedto those set forth herein.

(a). Dimethicone Copolyols or Alkyl Dimethicone Copolyols

One type of silicone surfactant that may be used is generally referredto as dimethicone copolyol or alkyl dimethicone copolyol. Thissurfactant is either a water-in-oil or oil-in-water surfactant having anHydrophile/Lipophile Balance (HLB) ranging from about 2 to 18.Preferably the silicone surfactant is a nonionic surfactant having anHLB ranging from about 2 to 12, preferably about 2 to 10, mostpreferably about 4 to 6. The term “hydrophilic radical” means a radicalthat, when substituted onto the organosiloxane polymer backbone, confershydrophilic properties to the substituted portion of the polymer.Examples of radicals that will confer hydrophilicity arehydroxy-polyethyleneoxy, hydroxyl, carboxylates, and mixtures thereof.The term “lipophilic radical” means an organic radical that, whensubstituted onto the organosiloxane polymer backbone, confers lipophilicproperties to the substituted portion of the polymer. Examples oforganic radicals that will confer lipophilicity are C₁₋₄₀ straight orbranched chain alkyl, fluoro, aryl, aryloxy, C₁₋₄₀ hydrocarbyl acyl,hydroxy-polypropyleneoxy, or mixtures thereof.

One type of suitable silicone surfactant has the general formula:

wherein p and q are from 0 to 40 (the range including all numbersbetween and sub-ranges such as 2, 3, 4, 13, 14, 15, 16, 17, 18, etc.),and PE is (—C₂H₄O)_(a)—(—C₃H₆O)_(b)—H, wherein a is from 0 to 25, b isfrom 0 to 25, with the proviso that a and b cannot both be 0simultaneously, wherein x, y and z are each independently ranging from 0to 1 million, with the proviso that they cannot all be 0 simultaneously.In one preferred embodiment, x, y, z, a, and b are such that themolecular weight of the polymer ranges from about 5,000 to about500,000, more preferably from about 10,000 to 100,000, and is mostpreferably approximately about 50,000 and the polymer is genericallyreferred to as dimethicone copolyol.

One type of silicone surfactant is wherein p is such that the long chainalkyl is cetyl or lauryl, and the surfactant is called, generically,cetyl dimethicone copolyol or lauryl dimethicone copolyol respectively.

In some cases the number of repeating ethylene oxide or propylene oxideunits in the polymer are also specified, such as a dimethicone copolyolthat is also referred to as PEG-15/PPG-10 dimethicone, which refers to adimethicone having substituents containing 15 ethylene glycol units and10 propylene glycol units on the siloxane backbone. It is also possiblefor one or more of the methyl groups in the above general structure tobe substituted with a longer chain alkyl (e.g. ethyl, propyl, butyl,etc.) or an ether such as methyl ether, ethyl ether, propyl ether, butylether, and the like.

Examples of silicone surfactants are those sold by Dow Corning under thetradename Dow Corning 3225C Formulation Aid having the CTFA namecyclotetrasiloxane (and) cyclopentasiloxane (and) PEG/PPG-18dimethicone; or 5225C Formulation Aid, having the CTFA namecyclopentasiloxane (and) PEG/PPG-18/18 dimethicone; or Dow Corning 190Surfactant having the CTFA name PEG/PPG-18/18 dimethicone; or DowCorning 193 Fluid, Dow Corning 5200 having the CTFA name laurylPEG/PPG-18/18 methicone; or Abil EM 90 having the CTFA name cetylPEG/PPG-14/14 dimethicone sold by Goldschmidt; or Abil EM 97 having theCTFA name bis-cetyl PEG/PPG-14/14 dimethicone sold by Goldschmidt; orAbil WE 09 having the CTFA name cetyl PEG/PPG-10/1 dimethicone in amixture also containing polyglyceryl-4 isostearate and hexyl laurate; orKF-6011 sold by Shin-Etsu Silicones having the CTFA name PEG-11 methylether dimethicone; KF-6012 sold by Shin-Etsu Silicones having the CTFAname PEG/PPG-20/22 butyl ether dimethicone; or KF-6013 sold by Shin-EtsuSilicones having the CTFA name PEG-9 dimethicone; or KF-6015 sold byShin-Etsu Silicones having the CTFA name PEG-3 dimethicone; or KF-6016sold by Shin-Etsu Silicones having the CTFA name PEG-9 methyl etherdimethicone; or KF-6017 sold by Shin-Etsu Silicones having the CTFA namePEG-10 dimethicone; or KF-6038 sold by Shin-Etsu Silicones having theCTFA name lauryl PEG-9 polydimethylsiloxyethyl dimethicone.

(b). Crosslinked Silicone Surfactants

Also suitable are various types of crosslinked silicone surfactants arereferred to as emulsifying elastomers. They are typically prepared asset forth above with respect to the section “silicone elastomers” exceptthat the silicone elastomers will contain at least one hydrophilicmoiety such as polyoxyalkylenated groups. Typically thesepolyoxyalkylenated silicone elastomers are crosslinkedorganopolysiloxanes that may be obtained by a crosslinking additionreaction of diorganopolysiloxane comprising at least one hydrogen bondedto silicon and of a polyoxyalkylene comprising at least twoethylenically unsaturated groups. In at least one embodiment, thepolyoxyalkylenated crosslinked organo-polysiloxanes are obtained by acrosslinking addition reaction of a diorganopolysiloxane comprising atleast two hydrogens each bonded to a silicon, and a polyoxyalkylenecomprising at least two ethylenically unsaturated groups, optionally inthe presence of a platinum catalyst, as described, for example, in U.S.Pat. No. 5,236,986 and U.S. Pat. No. 5,412,004, U.S. Pat. No. 5,837,793and U.S. Pat. No. 5,811,487, the contents of which are incorporated byreference.

Polyoxyalkylenated silicone elastomers that may be used in at least oneembodiment of the invention include those sold by Shin-Etsu Siliconesunder the names KSG-21, KSG-20, KSG-30, KSG-31, KSG-32, KSG-33; KSG-210which is dimethicone/PEG-10/15 crosspolymer dispersed in dimethicone;KSG-310 which is PEG-15 lauryl dimethicone crosspolymer; KSG-320 whichis PEG-15 lauryl dimethicone crosspolymer dispersed in isododecane;KSG-330 (the former dispersed in triethylhexanoin), KSG-340 which is amixture of PEG-10 lauryl dimethicone crosspolymer and PEG-15 lauryldimethicone crosspolymer.

Also suitable are polyglycerolated silicone elastomers like thosedisclosed in PCT/WO 2004/024798, which is hereby incorporated byreference in its entirety. Such elastomers include Shin-Etsu's KSGseries, such as KSG-710 which is dimethicone/polyglycerin-3 crosspolymerdispersed in dimethicone; or lauryl dimethicone/polyglycerin-3crosspolymer dispersed in a variety of solvent such as isododecane,dimethicone, triethylhexanoin, sold under the Shin-Etsu tradenamesKSG-810, KSG-820, KSG-830, or KSG-840. Also suitable are silicones soldby Dow Corning under the tradenames 9010 and DC9011.

One preferred crosslinked silicone elastomer emulsifier isdimethicone/PEG-10/15 crosspolymer.

2. Organic Surfactants

The composition may contain one or more additional surfactants, such asnonionic organic surfactants. Suitable nonionic surfactants includealkoxylated alcohols, or ethers, formed by the reaction of an alcoholwith an alkylene oxide, usually ethylene or propylene oxide. Preferablythe alcohol is either a fatty alcohol having 6 to 30 carbon atoms.Examples of such ingredients include Steareth 2-100, which is formed bythe reaction of stearyl alcohol and ethylene oxide and the number ofethylene oxide units ranges from 2 to 100; Beheneth 5-30 which is formedby the reaction of behenyl alcohol and ethylene oxide where the numberof repeating ethylene oxide units is 5 to 30; Ceteareth 2-100, formed bythe reaction of a mixture of cetyl and stearyl alcohol with ethyleneoxide, where the number of repeating ethylene oxide units in themolecule is 2 to 100; Ceteth 1-45 which is formed by the reaction ofcetyl alcohol and ethylene oxide, and the number of repeating ethyleneoxide units is 1 to 45, and so on.

Other alkoxylated alcohols are formed by the reaction of fatty acids andmono-, di- or polyhydric alcohols with an alkylene oxide. For example,the reaction products of C₆₋₃₀ fatty carboxylic acids and polyhydricalcohols which are monosaccharides such as glucose, galactose, methylglucose, and the like, with an alkoxylated alcohol. Examples includepolymeric alkylene glycols reacted with glyceryl fatty acid esters suchas PEG glyceryl oleates, PEG glyceryl stearate; or PEGpolyhydroxyalkanotes such as PEG dipolyhydroxystearate wherein thenumber of repeating ethylene glycol units ranges from 3 to 1000.

Also suitable as nonionic surfactants are formed by the reaction of acarboxylic acid with an alkylene oxide or with a polymeric ether. Theresulting products have the general formula: where RCO is the carboxylicester radical, X is hydrogen or lower alkyl, and n is the number ofpolymerized alkoxy groups. In the case of the diesters, the twoRCO-groups do not need to be identical. Preferably, R is a C₆₋₃₀straight or branched chain, saturated or unsaturated alkyl, and n isfrom 1-100.

Monomeric, homopolymeric, or block copolymeric ethers are also suitableas nonionic surfactants. Typically, such ethers are formed by thepolymerization of monomeric alkylene oxides, generally ethylene orpropylene oxide. Such polymeric ethers have the following generalformula: wherein R is H or lower alkyl and n is the number of repeatingmonomer units, and ranges from 1 to 500.

Other suitable nonionic surfactants include alkoxylated sorbitan andalkoxylated sorbitan derivatives. For example, alkoxylation, inparticular ethoxylation of sorbitan provides polyalkoxylated sorbitanderivatives. Esterification of polyalkoxylated sorbitan providessorbitan esters such as the polysorbates. For example, thepolyalkyoxylated sorbitan can be esterified with C₆₋₃₀, preferablyC₁₂₋₂₂ fatty acids. Examples of such ingredients include Polysorbates20-85, sorbitan oleate, sorbitan sesquioleate, sorbitan palmitate,sorbitan sesquiisostearate, sorbitan stearate, and so on.

Certain types of amphoteric, zwitterionic, or cationic surfactants mayalso be used in the compositions. Descriptions of such surfactants areset forth in U.S. Pat. No. 5,843,193, which is hereby incorporated byreference in its entirety.

D. Oil Phase Structuring Agents

If desired, the composition may contain one or more oil phasestructuring agents in the oil phase of the emulsion or anhydrouscomposition. The term “oil phase structuring agent” means an ingredientor combination of ingredients, soluble or dispersible in the oil phase,which will increase the viscosity, or structure, the oil phase. Thestructuring agent may be present in an amount sufficient to provide aliquid composition with increased viscosity, a semi-solid, or in somecases a solid composition that may be self-supporting. The structuringagent itself may be present in the liquid, semi-solid, or solid form.Suggested ranges of structuring agent are from about 0.01 to 70%,preferably from about 0.05 to 50%, more preferably from about 0.1-35% byweight of the total composition. Suitable oil phase structuring agentsinclude those that are silicone based or organic based. They may bepolymers or non-polymers, synthetic, natural, or a combination of both.

1. Silicone Structuring Agents

A variety of oil phase structuring agents may be silicone based, such assilicone elastomers, silicone gums, silicone waxes, linear siliconeshaving a degree of polymerization that provides the silicone with adegree of viscosity such that when incorporated into the cosmeticcomposition it is capable of increasing the viscosity of the oil phase.Examples of silicone structuring agents include, but are not limited to:

(a). Silicone Elastomers

Silicone elastomers suitable for use in the compositions of theinvention include those that are formed by addition reaction-curing, byreacting an SiH-containing diorganosiloxane and an organopolysiloxanehaving terminal olefinic unsaturation, or an alpha-omega dienehydrocarbon, in the presence of a platinum metal catalyst. Suchelastomers may also be formed by other reaction methods such ascondensation-curing organopolysiloxane compositions in the presence ofan organotin compound via a dehydrogenation reaction betweenhydroxyl-terminated diorganopolysiloxane and SiH-containingdiorganopolysiloxane or alpha omega diene; or by condensation-curingorganopolysiloxane compositions in the presence of an organotin compoundor a titanate ester using a condensation reaction between anhydroxyl-terminated diorganopolysiloxane and a hydrolysableorganosiloxane; peroxide-curing organopolysiloxane compositions whichthermally cure in the presence of an organoperoxide catalyst.

One type of elastomer that may be suitable is prepared by additionreaction-curing an organopolysiloxane having at least 2 lower alkenylgroups in each molecule or an alpha-omega diene; and anorganopolysiloxane having at least 2 silicon-bonded hydrogen atoms ineach molecule; and a platinum-type catalyst. While the lower alkenylgroups such as vinyl, can be present at any position in the molecule,terminal olefinic unsaturation on one or both molecular terminals ispreferred. The molecular structure of this component may be straightchain, branched straight chain, cyclic, or network. Theseorganopolysiloxanes are exemplified by methylvinylsiloxanes,methylvinylsiloxane-dimethylsiloxane copolymers,dimethylvinylsiloxy-terminated dimethylpolysiloxanes,dimethylvinylsiloxy-terminated dimethylsiloxane-methylphenylsiloxanecopolymers, dimethylvinylsiloxy-terminateddimethylsiloxane-diphenylsiloxane-methylvinylsiloxane copolymers,trimethylsiloxy-terminated dimethylsiloxane-methylvinylsiloxanecopolymers, trimethylsiloxy-terminateddimethylsiloxane-methylphenylsiloxane-methylvinylsiloxane copolymers,dimethylvinylsiloxy-terminatedmethyl(3,3,3-trifluoropropyl)polysiloxanes, anddimethylvinylsiloxy-terminateddimethylsiloxane-methyl(3,3,-trifluoropropyl)siloxane copolymers,decadiene, octadiene, heptadiene, hexadiene, pentadiene, or tetradiene,or tridiene.

Curing proceeds by the addition reaction of the silicon-bonded hydrogenatoms in the dimethyl methylhydrogen siloxane, with the siloxane oralpha-omega diene under catalysis using the catalyst mentioned herein.To form a highly crosslinked structure, the methyl hydrogen siloxanemust contain at least 2 silicon-bonded hydrogen atoms in each moleculein order to optimize function as a crosslinker.

The catalyst used in the addition reaction of silicon-bonded hydrogenatoms and alkenyl groups, and is concretely exemplified bychloroplatinic acid, possibly dissolved in an alcohol or ketone and thissolution optionally aged, chloroplatinic acid-olefin complexes,chloroplatinic acid-alkenylsiloxane complexes, chloroplatinicacid-diketone complexes, platinum black, and carrier-supported platinum.

Examples of suitable silicone elastomers for use in the compositions ofthe invention may be in the powder form, or dispersed or solubilized insolvents such as volatile or non-volatile silicones, or siliconecompatible vehicles such as paraffinic hydrocarbons or esters. Examplesof silicone elastomer powders include vinyl dimethicone/methiconesilesquioxane crosspolymers like Shin-Etsu's KSP-100, KSP-101, KSP-102,KSP-103, KSP-104, KSP-105, hybrid silicone powders that contain afluoroalkyl group like Shin-Etsu's KSP-200 which is a fluoro-siliconeelastomer, and hybrid silicone powders that contain a phenyl group suchas Shin-Etsu's KSP-300, which is a phenyl substituted siliconeelastomer; and Dow Corning's DC 9506. Examples of silicone elastomerpowders dispersed in a silicone compatible vehicle includedimethicone/vinyl dimethicone crosspolymers supplied by a variety ofsuppliers including Dow Corning Corporation under the tradenames 9040 or9041, GE Silicones under the tradename SFE 839, or Shin-Etsu Siliconesunder the tradenames KSG-15, 16, 18. KSG-15 has the CTFA namecyclopentasiloxane/dimethicone/vinyl dimethicone crosspolymer. KSG-18has the INCI name phenyl trimethicone/dimethicone/phenyl vinyldimethicone crosspolymer. Silicone elastomers may also be purchased fromGrant Industries under the Gransil trademark. Also suitable are siliconeelastomers having long chain alkyl substitutions such as lauryldimethicone/vinyl dimethicone crosspolymers supplied by Shin Etsu underthe tradenames KSG-31, KSG-32, KSG-41, KSG-42, KSG-43, and KSG-44.Cross-linked organopolysiloxane elastomers useful in the presentinvention and processes for making them are further described in U.S.Pat. No. 4,970,252 to Sakuta et al., issued Nov. 13, 1990; U.S. Pat. No.5,760,116 to Kilgour et al., issued Jun. 2, 1998; U.S. Pat. No.5,654,362 to Schulz, Jr. et al. issued Aug. 5, 1997; and Japanese PatentApplication JP 61-18708, assigned to Pola Kasei Kogyo KK, each of whichare herein incorporated by reference in its entirety.

(b). Silicone Gums

Also suitable for use as an oil phase structuring agent are one or moresilicone gums. The term “gum” means a silicone polymer having a degreeof polymerization sufficient to provide a silicone having a gum-liketexture. In certain cases the silicone polymer forming the gum may becrosslinked. The silicone gum typically has a viscosity ranging fromabout 500,000 to 100 million cst at 25° C., preferably from about600,000 to 20 million, more preferably from about 600,000 to 12 millioncst. All ranges mentioned herein include all subranges, e.g. 550,000;925,000; 3.5 million.

The silicone gums that are used in the compositions include, but are notlimited to, those of the general formula wherein:

R₁ to R₉ are each independently an alkyl having 1 to 30 carbon atoms,aryl, or aralkyl; and X is OH or a C₁₋₃₀ alkyl, or vinyl; and wherein x,y, or z may be zero with the proviso that no more than two of x, y, or zare zero at any one time, and further that x, y, and z are such that thesilicone gum has a viscosity of at least about 500,000 cst, ranging upto about 100 million centistokes at 25° C. Preferred is where R ismethyl or OH.

Such silicone gums may be purchased in pure form from a variety ofsilicone manufacturers including Wacker-Chemie or Dow Corning, and thelike. Such silicone gums include those sold by Wacker-Belsil under thetrade names CM3092, Wacker-Belsil 1000, or Wacker-Belsil DM 3096. Asilicone gum where X is OH, also referred to as dimethiconol, isavailable from Dow Corning Corporation under the trade name 1401. Thesilicone gum may also be purchased in the form of a solution ordispersion in a silicone compatible vehicle such as volatile ornonvolatile silicone. An example of such a mixture may be purchased fromBarnet Silicones under the HL-88 tradename, having the INCI namedimethicone.

(c). Silicone Waxes

Another type of oily phase structuring agent includes silicone waxesthat are typically referred to as alkyl silicone waxes which aresemi-solids or solids at room temperature. The term “alkyl silicone wax”means a polydimethylsiloxane having a substituted long chain alkyl (suchas C16 to 30) that confers a semi-solid or solid property to thesiloxane. Examples of such silicone waxes include stearyl dimethicone,which may be purchased from DeGussa Care & Surface Specialties under thetradename Abil Wax 9800 or from Dow Corning under the tradename 2503.Another example is bis-stearyl dimethicone, which may be purchased fromGransil Industries under the tradename Gransil A-18, or behenyldimethicone, behenoxy dimethicone.

2. Polyamides or Silicone Polyamides

Also suitable as oil phase structuring agents are various types ofpolymeric compounds such as polyamides or silicone polyamides.

The term silicone polyamide means a polymer comprised of siliconemonomers and monomers containing amide groups as further describedherein. The silicone polyamide preferably comprises moieties of thegeneral formula:

where X is a linear or branched alkylene having from about 1-30 carbonatoms; R₁, R₂, R₃, and R₄ are each independently C₁₋₃₀ straight orbranched chain alkyl which may be substituted with one or more hydroxylor halogen groups; phenyl which may be substituted with one or moreC₁₋₃₀ alkyl groups, halogen, hydroxyl, or alkoxy groups; or a siloxanechain having the general formula:

and Y is:

(a) a linear or branched alkylene having from about 1-40 carbon atomswhich may be substituted with (1) one or more amide groups having thegeneral formula R₁CONR₁, or (ii) C₅₋₆ cyclic ring, or (iii) phenylenewhich may be substituted with one or more C₁₋₁₀ alkyl groups, or (iv)hydroxy, or (v) C₃₋₈ cycloalkane, or (vi) C₁₋₂₀ alkyl which may besubstituted with one or more hydroxy groups, or (vii) C₁₋₁₀ alkylamities; or

(b) TR₅R₆R₇

wherein R₅, R₆, and R₇, are each independently a C₁₋₁₀ linear orbranched alkylenes, and T is CR₈ wherein R₈ is hydrogen, a trivalentatom N, P, or Al, or a C₁₋₃₀ straight or branched chain alkyl which maybe substituted with one or more hydroxyl or halogen groups; phenyl whichmay be substituted with one or more C₁₋₃₀ alkyl groups, halogen,hydroxyl, or alkoxy groups; or a siloxane chain having the generalformula:

Preferred is where R₁, R₂, R₃, and R₄ are C₁₋₁₀, preferably methyl; andX and Y is a linear or branched alkylene. Preferred are siliconepolyamides having the general formula

wherein a and b are each independently sufficient to provide a siliconepolyamide polymer having a melting point ranging from about 60 to 120°C., and a molecular weight ranging from about 40,000 to 500,000 Daltons.One type of silicone polyamide that may be used in the compositions ofthe invention may be purchased from Dow Corning Corporation under thetradename Dow Corning 2-8178 gellant which has the CTFA namenylon-611/dimethicone copolymer which is sold in a compositioncontaining PPG-3 myristyl ether.

Also suitable are polyamides such as those purchased from ArizonaChemical under the tradenames Uniclear and Sylvaclear. Such polyamidesmay be ester terminated or amide terminated. Examples of esterterminated polyamides include, but are not limited to those having thegeneral formula:

wherein n denotes a number of amide units such that the number of estergroups ranges from about 10% to 50% of the total number of ester andamide groups; each R₁ is independently an alkyl or alkenyl groupcontaining at least 4 carbon atoms; each R₂ is independently a C₄₋₄₂hydrocarbon group, with the proviso that at least 50% of the R₂ groupsare a C30-42 hydrocarbon; each R₃ is independently an organic groupcontaining at least 2 carbon atoms, hydrogen atoms and optionally one ormore oxygen or nitrogen atoms; and each R₄ is independently a hydrogenatom, a C₁₋₁₀ alkyl group or a direct bond to R₃ or to another R₄, suchthat the nitrogen atom to which R₃ and R₄ are both attached forms partof a heterocyclic structure defined by R₄—N—R₃, with at least 50% of thegroups R₄ representing a hydrogen atom.

General examples of ester and amide terminated polyamides that may beused as oil phase gelling agents include those sold by Arizona Chemicalunder the tradenames Sylvaclear A200V or A2614V, both having the CTFAname ethylenediamine/hydrogenated dimer dilinoleatecopolymer/bis-di-C₁₄₋₁₈ alkyl amide; Sylvaclear AF1900V; Sylvaclear C75Vhaving the CTFA name bis-stearyl ethylenediamine/neopentylglycol/stearyl hydrogenated dimer dilinoleate copolymer; SylvaclearPA1200V having the CTFA name Polyamide-3; Sylvaclear PE400V; SylvaclearWF1500V; or Uniclear, such as Uniclear 100VG having the INCI nameethylenediamine/stearyl dimer dilinoleate copolymer; orethylenediamine/stearyl dimer ditallate copolymer. Other examples ofsuitable polyamides include those sold by Henkel under the Versamidtrademark (such as Versamid 930, 744, 1655), or by Olin MathiesonChemical Corp. under the brand name Onamid S or Onamid C.

3. Natural or Synthetic Organic Waxes

Also suitable as the oil phase structuring agent may be one or morenatural or synthetic waxes such as animal, vegetable, or mineral waxes.Preferably such waxes will have a higher melting point such as fromabout 60 to 150° C., more preferably from about 65 to 100° C. Examplesof such waxes include waxes made by Fischer-Tropsch synthesis, such aspolyethylene or synthetic wax; or various vegetable waxes such asbayberry, candelilla, ozokerite, acacia, beeswax, ceresin, cetyl esters,flower wax, citrus wax, carnauba wax, jojoba wax, japan wax,polyethylene, microcrystalline, rice bran, lanolin wax, mink, montan,bayberry, ouricury, ozokerite, palm kernel wax, paraffin, avocado wax,apple wax, shellac wax, clary wax, spent grain wax, grape wax, andpolyalkylene glycol derivatives thereof such as PEG6-20 beeswax, orPEG-12 carnauba wax; or fatty acids or fatty alcohols, including estersthereof, such as hydroxystearie acids (for example 12-hydroxy stearicacid), tristearin, tribehenin, oleic acid, stearic acid, and so on.

4. Montmorillonite Minerals

One type of structuring agent that may be used in the compositioncomprises natural or synthetic montmorillonite minerals such ashectorite, bentonite, and quaternized derivatives thereof, which areobtained by reacting the minerals with a quaternary ammonium compound,such as stearalkonium bentonite, hectorites, quaternized hectorites suchas Quaternium-18 hectorite, attapulgite, carbonates such as propylenecarbonate, bentones, and the like.

5. Silicas and Silicates

Another type of structuring agent that may be used in the oil phase ofthe composition is silica, silicates, or silica silylate, and alkalimetal or alkaline earth metal derivatives thereof. These silicas andsilicates are generally found in the particulate form and includesilica, silica silylate, magnesium aluminum silicate, and the like.

E. Humectants

It may also be desirable to include one or more humectants in thecomposition. If present, such humectants may range from about 0.001 to25%, preferably from about 0.005 to 20%, more preferably from about 0.1to 15% by weight of the total composition. Examples of suitablehumectants include glycols in monomeric or polymeric form such aspolyethylene and polypropylene glycols such as PEG 4-200, which arepolyethylene glycols having from 4 to 200 repeating ethylene oxideunits; as well as C₁₋₆ alkylene glycols such as propylene glycol,butylene glycol, pentylene glycol, ethylhexylglycerin, trehalose,trehalose dihydrate, and the like. Preferably, the humectants used inthe composition of the invention are C₁₋₆, preferably C₂₋₄ alkyleneglycols, most particularly butylene glycol.

F. Aqueous Phase Structuring Agents

If the compositions of the invention contain an aqueous phase it may bedesirable to include one or more aqueous phase structuring agents in thecomposition. Such agents will typically thicken or increase theviscosity of the aqueous phase. If present, suggested ranges are fromabout 0.01 to 30%, preferably from about 0.1 to 20%, more preferablyfrom about 0.5 to 15% by weight of the total composition. Examples ofsuch agents include various acrylate based thickening agents, natural orsynthetic gums, and the like.

1. Acrylate Polymers

For example, acrylic polymeric thickeners comprised of monomers A and Bwherein A is selected from the group consisting of acrylic acid,methacrylic acid, and mixtures thereof; and B is selected from the groupconsisting of a C₁₋₂₂ alkyl acrylate, a C₁₋₂₂ alky methacrylate, andmixtures thereof are suitable. In one embodiment the A monomer comprisesone or more of acrylic acid or methacrylic acid, and the B monomer isselected from the group consisting of a most preferably C₁₋₄ alkylacrylate, a C₁₋₁₀, most preferably C₁₋₄ alkyl methacrylate, and mixturesthereof. Most preferably the B monomer is one or more of methyl or ethylacrylate or methacrylate. The acrylic copolymer may be supplied in anaqueous solution having a solids content ranging from about 10-60%,preferably 20-50%, more preferably 25-45% by weight of the polymer, withthe remainder water. The composition of the acrylic copolymer maycontain from about 0.1-99 parts of the A monomer, and about 0.1-99 partsof the B monomer. Acrylic polymer solutions include those sold bySeppic, Inc., under the tradename Capigel.

Also suitable are acrylic polymeric thickeners that are copolymer of A,B, and C monomers wherein A and B are as defined above, and C has thegeneral formula:

wherein Z is —(CH₂)_(m); wherein in is 1-10, n is 2-3, o is 2-200, and Ris a C₁₀₋₃₀ straight or branched chain alkyl. Examples of the secondarythickening agent above, are copolymers where A and B are defined asabove, and C is CO, and wherein n, o, and R are as above defined.Examples of such secondary thickening agents includeacrylates/steareth-20 methacrylate copolymer, which is sold by Rohm &Haas under the tradename Acrysol ICS-1.

Also suitable are acrylate based anionic amphiphilic polymers containingat least one hydrophilic unit and at least one allyl ether unitcontaining a fatty chain. Preferred are those where the hydrophilic unitcontains an ethylenically unsaturated anionic monomer, more specificallya vinyl carboxylic acid such as acrylic acid, methacrylic acid ormixtures thereof, and where the allyl ether unit containing a fattychain corresponds to the monomer of formula:CH₂═CR′CH₂OB_(n)Rin which R′ denotes H or CH₃, B denotes the ethylenoxy radical, n iszero or an integer ranging from 1 to 100, R denotes a hydrocarbonradical selected from alkyl, arylalkyl, aryl, alkylaryl and cycloalkylradicals which contain from 8 to 30 carbon atoms, preferably from 10 to24, and even more particularly from 12 to 18 carbon atoms. Morepreferred in this case is where R′ denotes H, n is equal to 10 and Rdenotes a stearyl (C18) radical. Anionic amphiphilic polymers of thistype are described and prepared in U.S. Pat. Nos. 4,677,152 and4,702,844, both of which are hereby incorporated by reference in theirentirety. Among these anionic amphiphilic polymers, polymers formed of20 to 60% by weight acrylic acid and/or methacrylic acid, of 5 to 60% byweight lower alkyl methacrylates, of 2 to 50% by weight allyl ethercontaining a fatty chain as mentioned above, and of 0 to 1% by weight ofa crosslinking agent which is a well-known copolymerizable polyethylenicunsaturated monomer, for instance diallyl phthalate,allyl(meth)acrylate, divinylbenzene, (poly)ethylene glycoldimethacrylate and methylenebisacrylamide. One commercial example ofsuch polymers are crosslinked terpolymers of methacrylic acid, of ethylacrylate, of polyethylene glycol (having 10 EO units) ether of stearylalcohol or steareth-10, in particular those sold by the company AlliedColloids under the names SALCARE SC80 and SALCARE SC90, which areaqueous emulsions containing 30% of a crosslinked terpolymer ofmethacrylic acid, of ethyl acrylate and of steareth-10 allyl ether(40/50/10).

Also suitable are acrylate copolymers such as Polyacrylate-3 which is acopolymer of methacrylic acid, methylmethacrylate, methylstyreneisopropylisocyanate, and PEG-40 behenate monomers; Polyacrylate-10 whichis a copolymer of sodium acryloyldimethyltaurate, sodium acrylate,acrylamide and vinyl pyrrolidone monomers; or Polyacrylate-11, which isa copolymer of sodium acryloyldimethylacryloyldimethyl taurate, sodiumacrylate, hydroxyethyl acrylate, lauryl acrylate, butyl acrylate, andacrylamide monomers.

Also suitable are crosslinked acrylate based polymers where one or moreof the acrylic groups may have substituted long chain alkyl (such as6-40, 10-30, and the like) groups, for example acrylates/C₁₀₋₃₀ alkylacrylate crosspolymer which is a copolymer of C10-30 alkyl acrylate andone or more monomers of acrylic acid, methacrylic acid, or one of theirsimple esters crosslinked with the allyl ether of sucrose or the allylether of pentaerythritol. Such polymers are commonly sold under theCarbopol or Pemulen tradenames.

Particularly suitable as the aqueous phase thickening agent are acrylatebased polymeric thickeners sold by Clariant under the Aristoflextrademark such as Aristoflex AVC, which is ammoniumacryloyldimethyltaurate/VP copolymer; Aristoflex AVL which is the samepolymer has found in AVC dispersed in mixture containing caprylic/caprictriglyceride, trilaureth-4, and polyglyceryl-2 sesquiisostearate; orAristoflex HMB which is ammonium acryloyldimethyltatirate/beheneth-25methacrylate crosspolymer, and the like.

2. High Molecular Weight PEG or Polyglycerins

Also suitable as the aqueous phase thickening agents are variouspolyethylene glycols (PEG) derivatives where the degree ofpolymerization ranges from 1,000 to 200,000. Such ingredients areindicated by the designation “PEG” followed by the degree ofpolymerization in thousands, such as PEG-45M, which means PEG having45,000 repeating ethylene oxide units. Examples of suitable PEGderivatives include PEG 2M, 5M, 7M, 9M, 14M, 20M, 23M, 25M, 45M, 65M,90M, 115M, 160M, 180M, and the like.

Also suitable are polyglycerins which are repeating glycerin moietieswhere the number of repeating moieties ranges from 15 to 200, preferablyfrom about 20-100. Examples of suitable polyglycerins include thosehaving the CFTA names polyglycerin-20, polyglycerin-40, and the like.

3. Polysaccharides

Also suitable as aqueous phase thickening agents are various types ofpolysaccharides, such as xanthan gum, cellulose, dextrin, cyclodextrin,hydroxyethylcellulose, acacia gum, and the like.

G. Botanical Extracts

It may be desirable to include one or more botanical extracts in thecompositions in addition to those botanical extracts that have kinaseinhibitor activity. If so, suggested ranges are from about 0.0001 to10%, preferably about 0.0005 to 8%, more preferably about 0.001 to 5% byweight of the total composition. Suitable botanical extracts includeextracts from plants (herbs, roots, flowers, fruits, seeds) such asflowers, fruits, vegetables, and so on, including yeast ferment extract,padica pavonica extract, thermos thermophilis ferment extract, camelinasativa seed oil, boswellia serrata extract, olive extract, aribodopsisthaliana extract, acacia dealbata extract, acer saccharinum (sugarmaple), acidopholus, acorus, aesculus, agaricus, agave, agrimonia,algae, aloe, citrus, brassica, cinnamon, orange, apple, blueberry,cranberry, peach, pear, lemon, lime, pea, seaweed, caffeine, green tea,chamomile, willowbark, mulberry, rosemary, poppy, and the like. Furtherspecific examples include, but are not limited to, Glycyrrhiza Glabra,Salix Nigra, Macrocycstis Pyrifera, Pyrus Malus, Saxifraga Sarmentosa,Vilis Vinifera, Moms Nigra, Scutellaria Baicalensis, Anthemis Nobilis,Salvia Sclarea, Citrus Medica Limonum, Panax Ginseng, and mixturesthereof.

H. Particulate Materials

The compositions of the invention may contain particulate materials inthe form of pigments, inert particulates, or mixtures thereof. Ifpresent, suggested ranges are from about 0.1-75%, preferably about0.5-70%, more preferably about 0.1-65% by weight of the totalcomposition. In the case where the composition may comprise mixtures ofpigments and powders, suitable ranges include about 0.01-75% pigment and0.1-75% powder, such weights by weight of the total composition.

1. Powders

The particulate matter may be colored or non-colored (for example white)non-pigmentations powders. Suitable non-pigmentations powders includebismuth oxychloride, titanated mica, fumed silica, spherical silica,polymethylmethacrylate, micronized teflon, boron nitride, acrylatecopolymers, aluminum silicate, aluminum starch octenylsuccinate,bentonite, calcium silicate, cellulose, chalk, corn starch, diatomaceousearth, fuller's earth, glyceryl starch, hectorite, hydrated silica,kaolin, magnesium aluminum silicate, magnesium trisilicate,maltodextrin, montmorillonite, microcrystalline cellulose, rice starch,silica, talc, mica, titanium dioxide, zinc laurate, zinc myristate, zincrosinate, alumina, attapulgite, calcium carbonate, calcium silicate,dextran, kaolin, nylon, silica silylate, silk powder, sericite, soyflour, tin oxide, titanium hydroxide, trimagnesium phosphate, walnutshell powder, or mixtures thereof. The above mentioned powders may besurface treated with lecithin, amino acids, mineral oil, silicone, orvarious other agents either alone or in combination, which coat thepowder surface and render the particles more lipophilic in nature.

2. Pigments

The particulate materials may comprise various organic and/or inorganicpigments. The organic pigments are generally various aromatic typesincluding azo, indigoid, triphenylmethane, anthroquinone, and xanthinedyes which are designated as D&C and FD&C blues, browns, greens,oranges, reds, yellows, etc. Organic pigments generally consist ofinsoluble metallic salts of certified color additives, referred to asthe Lakes. Inorganic pigments include iron oxides, ultramarines,chromium, chromium hydroxide colors, and mixtures thereof. Iron oxidesof red, blue, yellow, brown, black, and mixtures thereof are suitable.

I. Preservatives

The composition may contain 0.001-8%, preferably 0.01-6%, morepreferably 0.05-5% by weight of the total composition of preservatives.A variety of preservatives are suitable, including such as benzoic acid,benzyl alcohol, benzythemiformal, benzylparaben,5-bromo-5-nitro-1,3-dioxane, 2-bromo-2-nitropropane-1,3-diol, butylparaben, phenoxyethanol, methyl paraben, propyl paraben, diazolidinylurea, calcium benzoate, calcium propionate, caprylyl glycol, biguanidederivatives, phenoxyethanol, captan, chlorhexidine diacetate,chlorhexidine digluconate, chlorhexidine dihydrochloride,chloroacetamide, chlorobutanol, p-chloro-m-cresol, chlorophene,chlorothymol, chloroxylenol, m-cresol, o-cresol, DEDM Hydantoin, DEDMHydantoin dilaurate, dehydroacetic acid, diazolidinyl urea,dibromopropamidine diisethionate, DMDM Hydantoin, and the like. In onepreferred embodiment the composition is free of parabens.

J. Vitamins and Antioxidants

The compositions of the invention, may contain vitamins and/orcoenzymes, as well as antioxidants. If so, 0.001-10%, preferably0.01-8%, more preferably 0.05-5% by weight of the total composition aresuggested. Suitable vitamins include ascorbic acid and derivativesthereof, the B vitamins such as thiamine, riboflavin, pyridoxin,panthenol, and so on, as well as coenzymes such as thiaminepyrophoshate, flavin adenin dinucleotide, folic acid, pyridoxalphosphate, tetrahydrofolic acid, and so on. Also Vitamin A andderivatives thereof are suitable. Examples are Vitamin A palmitate,acetate, or other esters thereof, as well as Vitamin A in the form ofbeta carotene. Also suitable is Vitamin E and derivatives thereof suchas Vitamin E acetate, nicotinate, or other esters thereof. In addition,Vitamins D and K are suitable.

Suitable antioxidants are ingredients which assist in preventing orretarding spoilage. Examples of antioxidants suitable for use in thecompositions of the invention are potassium sulfite, sodium bisulfite,sodium erythrobate, sodium metabisulfite, sodium sulfite, propylgallate, cysteine hydrochloride, butylated hydroxytoluene, butylatedhydroxyanisole, and so on.

K. Film Forming Polymers

In certain cases it is desirable to include film forming polymers in thecompositions of the invention. If present, the polymers may range fromabout 0.01 to 85%, preferably from about 0.1 to 75%, preferably fromabout 0.5 to 40% by weight of the total compositions. Such polymers maysilicones, copolymers of silicones and organic groups, or polymers orcopolymers containing entirely organic groups. Examples of organicmonomers that may be used to construct suitable film forming polymersinclude styrene, vinyl pyrrolidone, acrylic or methacrylic acid or itsC₁₋₁₀ simple esters such as methyl methacrylate, methylacrylate, ethylmethacrylate, ethylacrylate, butyl acrylate, butyl methacrylate, and soon. The organic monomers may be neutralized with sales such as ammonia,sodium, potassium, and the like (e.g. ammonium acrylate, ammoniummethacrylate, sodium acrylate, sodium methacrylate, and the like). Theorganic monomers may be copolymerized with other organic ingredientssuch as glycols, fatty acids, esters like those mentioned herein.Suitable film forming polymers also include copolymers of organicmonomers and silicone, including a class of polymers generally referredto as silicone acrylate copolymers. One example of such polymersincludes polydimethylsiloxane-g-polyacrylates sold by 3M Company underthe tradename VS-70. Also suitable are silicone film forming polymers,including a group of silicones referred as silicone resins(trimethylsiloxysilicate or polymethylsilsesquioxane). A variety of filmforming polymers may be used in the compositions of the inventiondepending on the desired end benefit.

The invention will be further described in connection with the followingexamples which are set forth for the purposes of illustration only.

Example 1

Ingredients were selected that had inhibitory activity for each of the11 Pathways mentioned above were selected using the test methods setforth herein, and combined to form an ingredient mixture as follows:

Ingredient Pathway Inhibited % by weight Grapefruit Peel extractHistamine Pathway 0.10 Gorgonian Extract PLA-1 Pathway 0.50Nordihydroguaiaretic Acid 5-LO Pathway 0.02 Resveratrol COX-2 Pathway0.10 Fucoidan YSK Chemotaxis Pathway 0.10 (Cladosiphon Okamuranusextract) Polysea PF (Algae extract) Adhesion Pathway 0.50 SiegesbeckiaOrientalis Collagenase Pathway 0.20 White Birch extract Elastase Pathway0.10 18-B-glycerrhetinic acid PDE Pathway 0.10 Magnolia extract VEGFPathway 0.05 Mangostin or Garcinia Histamine Receptor Pathway 0.10Mangostana Peel extract (Xanomax ®)

Example 2

Various compositions containing the combination in Example 1 were testedfor ability to inhibit or curtail skin inflammation. The testcompositions were prepared as follows:

Formula Formula 7666/4 New Formula 7666/1 Formula Mag 7666/3P Old 7666/3New Ingredient % by weight Hydrogenated 1.00 1.00 — 1.00 lecithin NDGA¹0.02 — 0.50 0.02 Magnolia 0.05 — 0.05 0.05 Officianalis Bark Extract²Butylene 0.50 — 0.50 0.50 glycol/Gorgonian (Sea Whip) extract³ BHT — —0.05 — Ammonium 1.00 1.00 1.00 1.00 acrylodimethyl- taurate copolymerSqualane 3.00  0.018 3.00 3.00 Glycyrrhetinic 0.10 — 0.10 0.10 acid⁴Phenoxyethanol 0.52 0.03  0.048 0.52 Disodium 0.10 — 0.10 0.10 EDTACetyl alcohol 0.50 0.50 0.50 0.50 Cladosiphon 0.50 — 0.10 0.10Okamuranus extract/dextrin (Fucoidan YSK)⁴ Algae extract 0.50 — 0.500.50 (Polysea PF)⁵ Dimethicone 1.00 1.00 — 1.00 Dimethicone/ — — 1.00 —dimethiconol Cetearyl alcohol 1.00 1.00 1.00 1.00 Butylene glycol 9.009.00 9.00 9.00 Garcinia 0.10 — 0.10 0.10 Mangostana Peel extract(Mangostin)⁶ Caprylyl 1.00 1.00 1.00 1.00 glycol/phenoxy-ethanol/hexylene glycol Xanthan gum 0.20 0.20 0.20 0.20 Cetearyl 3.003.00 3.00 3.00 alcohol/ Cetearyl glucoside Tromethane 0.20 0.20 0.200.20 Carbomer 0.20 0.20 0.20 0.20 PEG-6 4.00 4.00 4.00 4.00Polyglyceryl-3 0.50 0.50 — 0.50 beeswax Behenyl alcohol 1.00 1.00 1.001.00 Isostearyl 3.00 3.00 3.00 3.00 neopentanoate Hyaluronic acid 0.020.02 0.02 0.02 powder - sodinin salt Citrus Grandis 0.10 — 0.10 0.10(Grapefruit) peel extract⁷ Polygonum 0.10 — 0.10 0.10 Cuspidatum extract(resveratrol)⁸ Shea butter 2.00 2.00 2.00 2.00 Siegesbeckia 0.20 — 0.200.20 Orientalis extract⁹ Betula Alba 0.10 — 1.00 0.10 (White Birch)extract¹⁰ Glycerin 6.00 6.00 6.00 6.00 Water QS 100 QS 100 QS 100 QS 100¹Nordihydroguaiaretic acid, a 5-LO Pathway Inhibitor ²VEGF PathwayInhibitor ³PLA-1 Pathway Inhibitor. Sea Whip extract is also known asGorgonian extract ⁴PDE Pathway Inhibitor ⁵Fucoidan YSK, a ChemotaxisPathway Inhibitor ⁶Polysea PF, an Adhesion Pathway Inhibitor ⁷Mangostin,a Histamine Receptor Pathway Inhibitor ⁸Histamine Pathway Inhibitor⁹COX-2 Pathway Inhibitor ¹⁰Collagenase Pathway Inhibitor ¹¹ElastasePathway InhibitorAlso tested were:Cola: Cola nitidia extract in 10% hydroalcoholic solutionHydrocortisone: 1% hydrocortisone cream purchased from CVS pharmacy.

Seven volunteers with a history of skin sensitivity to Balsam of Peruwere chosen for the study. 1.5 inch square areas were marked on thevolar forearms of the subjects; with one of the areas corresponding tothe untreated control. The test materials were applied on the respectivesites and after 20 minutes, Balsam of Peru was applied at the rate ofapproximately 4 mg/cm2 in a 1.5 cm diameter circle. When rednessappeared the Balsam of Peru was wiped off with a wet towel and thedegree of redness measured with a Minolta Chromometer. The results areshown in the FIGURE. The “Percent Activity” refers to the activity ofeach composition in inhibiting inflammation. The Cola Nitidiacomposition is a known inflammation inhibitor. It is seen that thecompositions of the invention (7666/4 New Mag; 7666/1 Old; and 7666/3New) are significantly more effective in inhibiting inflammation thatcomposition 7666/3P and 1% hydrocortisone cream sold over the counter,the latter being a well known treatment for skin inflammation.

Example 3

A skin care lotion according to the invention was prepared as follows:

w/w Ingredient % Garcinia Mangostana Peel extract (Histamine ReceptorPathway) 0.10 Betula Alba extract (Elastase Pathway) 0.10 Citris Grandis(Grapefruit) Peel extract (Histamine Pathway) 0.10 Xanthan gum 0.20Tromethamine 0.20 Shea butter 2.00 Siegesbeckia Orientalisextract/glycerin (Collagenase Pathway) 0.20 Dimethicone 1.00 PolygonumCuspidatum extract (COX Pathway) 0.10 Algae extract (Polysea PF)(Adhesion Pathway) 0.50 Phenoxyethanol 0.02 PEG-6 4.00Norhydroguaiaretic acid (LO Pathway) 0.02 Cetearyl alcohol/cetearylglucoside 3.00 Hydrogenated lecithin 1.00 Sodium hyaluronate 0.02Butylene glycol/Sea Whip extract 0.50 Glycerin 6.00 CladosiphonOkamuronus extract/dextran 0.10 Squalane 3.00 Phenoxyethanol 0.03Caprylyl glycol/phenoxyethanol/hexylene glycol 1.00 Disodium EDTA 0.10Cetearyl alcohol 1.00 Water QS Polyglyceryl-3 beeswax 0.50 Cetyl alcohol0.50 Isostearyl neopentanoate 3.00 Carbomer (Carbopol 980) 0.20 Behenylalcohol 1.00 Butylene glycol 9.00 Ammonium acryloyldimethyltaurate/VPcopolymer 1.00 Magnolia Officianalis Bark extract (VEGF Pathway) 0.05

The composition was prepared by combining the ingredients and mixingwell to form a lotion. The lotion contains selected ingredients thatinhibit each of the 11 Pathways as identified herein.

Example 4

SPF containing redness relief creams were prepared as follows:

w/w % Ingredient 1 2 Cholesterol/potassium sulfate 0.10 Wheat (TriticumVulgare) Bran Extract/Olive (Olea 0.20 Europaea) Extract Laureth-23 0.17Dimethicone/trisiloxane 3.00 Water/ethylhexyl palmitate/butylene 1.001.00 glycol/cholesterol/astrocaryum murmuru butter/ linoleic acid coffeerobusta seed extract/ ethylhexyl stearate/carbomer/ propylene glycoldicaprylate/phytosphingosine (Chemotaxis Pathway Inhibitor)Caprylic/capric/myristic/stearic triglyceride 3.00 Ethylhexyl salicylate5.00 5.00 Aminopropyl ascorbyl phosphate 0.10 0.10 Cholesterol 0.20Glycerin/Padina Pavonica extract 0.10 0.10 Butylene glycol/Sea Whip(Gorgonian) extract 0.50 0.50 (PLA-2 Pathway Inhibitor) Water/decarboxycarnosine HCl/butylene glycol 0.20 0.20 (Alistin) Camomilla Recutita(Matricaria) Flower extract 0.017 0.012 (COX-2 Pathway Inhibitor)Water/butlene glycol/lecithin/C1-8 alkyl 1.00tetrahydroxycyclohexanoate/Rosmarinus Officianalis (Rosemary)extract/Ascorbyl tocopheryl maleate/maltodextrin/lauryldimoniumhydroxypropyl hydrolyzed soy (Histamine Pathway Inhibitor)Water/butylene glycol/disodium NADH/lecithin/ 1.00 C1-8 alkyltetrahydroxycyclohexanoate/Rosmarinus Officinalis (Rosemary) Extract,Ascorbyl tocopheryl maleate/maltodextrin/lauryldimonium hydroxypropylhydrolyzed soy protein Dimethicone 1.50 Dimethicone/Polysilicone-11 6.00Silica 2.00 Ammonium Acryloydimethyltaurate/VP Copolymer 0.95 1.00Trehalose 0.50 0.50 PEG-100 stearate 1.50 Echinacea Pallida (Coneflower)Extract (VEGF 0.001 0.001 Pathway Inhibitor) Zeolite 0.10 0.10Phenoxyethanol 0.009 Polysorbate 20 0.20 Disodium EDTA 0.10 AlgaeExtract (Polysea PF) (Adhesion Pathway 0.50 0.50 Inhibitor) Polyester-83.00 2.32 Linoleic acid 0.20 0.20 Glyceryl stearate 1.50 Butylene glycol0.50 3.00 Sucrose 0.50 0.50 Polyglyceryl-2 Triisostearate 3.00Avobenzone 3.00 3.00 Sodium Ribonucleic Acid 0.20 0.20 Tocopherylacetate 0.50 0.50 Octocrylene 1.39 Caprylylglycol/phenoxyethanol/hexylene glycol 0.80 Tromethane 0.07 0.08Acrylamide/Sodium acryloyldimethyltaurate 0.90copolymer/Isohexadecane/Polysorbate 80 Acrylic acid/VP crosspolymer 0.10Behenyl alcohol 1.00 Dimethicone 3.00 Caffeine 0.18 0.20 Water/butyleneglycol/Laminaria Saccharina extract 0.50 Sodium hyaluronate 0.10 0.01Benzophenone-3 5.00 5.00 Water/lecithin/micrococcus lysate 0.10 0.10Laureth-4 0.685 Dimethicone 0.75 Butyloctyl salicylate 3.50 3.50Isononyl isononanoate 3.00 Astrocaryum Murmuru Butter 0.20 Steareth-210.90 Polyethylene 0.50 0.0001 Isopropyl PPG-2-Isodeceth-7 Carboxylate3.50 Sodium chloride 0.0001 0.0001 Petrolatum 5.00 Sodium EDTA 0.10Glycerin 1.50 Water QS 100 QS 100

Composition 1 contains 6 Pathway Inhibitors and Composition 2 contains 5Pathway Inhibitors. The compositions are prepared by combining theingredients and mixing well to form emulsions.

While the invention has been described in connection with the preferredembodiment, it is not intended to limit the scope of the invention tothe particular form set forth but, on the contrary, it is intended tocover such alternatives, modifications, and equivalents as may beincluded within the spirit and scope of the invention as defined by theappended claims.

The invention claimed is:
 1. A method for reducing redness, pain or heatin intact skin in need of such treatment by topically applying to theskin a composition free of hydrocortisone in the form of anhydrous,emulsion, or gel composition comprising: at least one botanic extractthat inhibits the Histamine pathway when topically applied; at least onebotanic extract that inhibits the Phospholipase A2 pathway whentopically applied, at least one botanic extract that inhibits theCyclooxygenase 2 pathway when topically applied, at least one botanicextract that inhibits the Vascular Endothelial Growth Factor pathwayinhibitor when topically applied, at least one botanic extract thatinhibits the Histamine Receptor pathway when topically applied, at leastone botanic extract that inhibits the Lipoxygenase pathway-whentopically applied; and at least one botanic extract that inhibits theChemotaxis pathway when topically applied, wherein the compositioncontaining the combined pathway inhibitors has an effectiveness inreducing the redness, pain, or heat that is equal to or greater than theidentical composition containing 1% hydrocortisone and being free of thecombined pathway inhibitors.
 2. The method of claim 1 wherein theinhibitor of the Histamine pathway is in the form of a botanical extracthaving a component selected from the group consisting of flavones,apigenins, flavonoids, luteolins, phloretins, chalcones and mixturesthereof.
 3. The method of claim 1 wherein the inhibitor of thePhospholipase A2 pathway is selected from the group consisting ofLyngbya extract; grapeseed extract; licochalcone; Viapure poria extract;Polyporus umbellatus; avocado extract; Camellia sinensis; Chrysanthellumindicum; Tridentata marginata extract; Pomegranate extract; Gorgonianextract; and mixtures thereof.
 4. The method of claim 1 wherein theinhibitor of the Cyclooxygenase 2 pathway is selected from the groupconsisting of Acacia genus; Calluna Vulgaris; Rosa Canina fruit extract;nettle leaf extract; Polyporus Umbellatus; Chamomilla Recutita(Matricaria) flower oil; a mixture of Butcher's Broom extract andheperidin methyl chalcone; resveratrol; HOP's beta acids; and mixturesthereof.
 5. The method of claim 1 wherein the inhibitor of the VascularEndothelial Growth Factor pathway is selected from the group consistingof the Saussurea genus such as Saussurea Costus extract, SaussureaLappa; Sesquiterpene lactones; magnolia extract; a mixture of butyleneglycol, water, and Cynara Scolymus (Artichoke) Leaf Extract);hypoestoxide (HE); Magnolia Officianalis Bark extract; EchineaceaPallida extract; and mixtures thereof.
 6. The method of claim 1 whereinthe inhibitor of the Lipooxygenase pathway is selected from the groupconsisting of Haplophyllum hispanicum Spach; Scutellaria Rivularisextract; alpha ketoboswellic acid; Zileuton®(1-(1-benzothiophen-2-ylethyl)-1-hydroxy-urea); Centaurium extract;nordihydroguaiaretic acid; ginger oil; resveratrol; Polygonum Cuspidatumextract; cedar himalaya extract; tetrahydrocurcuminoids; Nigella Sativaessential oil; copaiba balsam; Australian sandalwood; Rhodiola Rosea;frankincense; blue cypress oil; blue chamomile oil; vetiver mada;bulgarian rose oil; Helichrysum oil; rosmarinic acid; resveratroltriphosphate; noni leaf extract; and mixtures thereof.
 7. The method ofclaim 1 wherein the inhibitor of the Chemotaxis pathway is selected fromthe group consisting of licorice extract; genestein; extracts from thegenus Scutellaria; extracts from the Boswellia genus; extract from theCommiphora genus; Bursera Microphylla; Nidularium Procerum; sequoiaextract; hypoestoxide; Curcuma Longa (turmeric) extract; butyloctylsalicylate; abyssine; plai oil; geranium bourbon oil; jiagolun EX;fucoidan YSK; caffeine; galactoarabinan; lion's mane mushroom extract;clerilys; extracts from Macrycystis Pyrifera; reishi mushroom extract;Pleurotus Ostreatus extract; Hypsizygus Ulmarius extract; CladosiphonOkamuranus Extract; Acalypha Wilkesiana extract; AcanthopanaxGracilistylus extract; Allium Sativum extract; Ananus Comosus extract;Cissampelos Sympodialis extract; Coriolus Versicolor extract; EchinaceaPurpurea extract; Grifola Frondosa extract; Harpagophytum Procumbensextract; Panax Ginseng extract; Polygala Tenuifolia extract; Poria Cocosextract; Silybum Marianum extract; Smilax Glabra extract; TinosporaCordifolia extract; Uncaria Tomentosa extract; Withania Somniferaextract; slime mold; Echinancea extract; Viscum Album extract; coffeerobusta seed extract; capsaicin; a hexapeptide having the amino acidsequence (SEQ ID NO: 1) Val-Gly-Val-Ala-Pro-Gly (VGVAPG); ubiquitin;nicotinalides; cytochalasin B; and mixtures thereof.
 8. The method ofclaim 1 additionally comprising at least one botanic extract thatinhibits the Adhesion pathway when topically applied.
 9. The method ofclaim 1 additionally comprising at least one botanic extract thatinhibits the Collagenase pathway when topically applied.
 10. A methodfor reducing redness, pain or heat in intact skin in need of suchtreatment by topically applying to the skin a composition free ofhydrocortisone in the form of anhydrous, or emulsion, or gel compositioncomprising: at least one Histamine pathway inhibitor in the form of abotanical extract having a component selected from the group consistingof flavones, apigenins, flavonoids, luteolins, phloretins, chalcones,and mixtures thereof; at least one Phospholipase A2 pathway inhibitor inthe form of a botanical extract having a component selected from thegroup consisting of amentoflavone, licochalcone, ellagic acid,hesperitin, polyphenol, and mixtures thereof; at least oneCyclooxygenase-2 pathway inhibitor in the form of a botanical extractfrom the Acacia genus, Calluna genus, Rosa genus, Polyporus genus,Chamomilla genus, nettle leaf, Butcher's broom; hesperidin, methylchalcone, resveratrol, HOPS beta acids, and mixtures thereof; at leastone Vascular Endothelial Growth Factor pathway inhibitor in the form ofa botanical extract selected from the group consisting of Saussureagenus, Magnolia genus, Cynara genus, Echineacea genus, Pallida genus;sesquiterpene lactones, hypoestoxide, and mixtures thereof; at least oneHistamine receptor pathway inhibitor in the form of a botanical extractselected from the group consisting of Japanese Butterbur, Garciniagenus, and mixtures thereof; at least one Lipoxygenase pathway inhibitorselected from the group consisting of Haplophyllum hispanicum Spach;Scutellaria Rivularis extract; alpha ketoboswellic acid; Zileuton®(1-(1-benzothiophen-2-ylethyl)-1-hydroxy-urea); Centaurium extract;nordihydroguaiaretic acid; ginger oil; resveratrol; Polygonum Cuspidatumextract; cedar himalaya extract; tetrahydrocurcuminoids; Nigella Sativaessential oil; copaiba balsam; Australian sandalwood; Rhodiola Rosea;frankincense; blue cypress oil; blue chamomile oil; vetiver mada;bulgarian rose oil; Helichrysum oil; rosmarinic acid; resveratroltriphosphate; noni leaf extract; and mixtures thereof; and at least oneChemotaxis pathway inhibitor selected from the group consisting oflicorice extract; genestein; extracts from the genus Scutellaria;extracts from the Boswellia genus; extract from the Commiphora genus;Bursera Microphylla extract; Nidularium Proceru extract; sequoiaextract; hypoestoxide; Curcuma Longa (turmeric) extract; butyloctylsalicylate; abyssine; plai oil; geranium bourbon oil; jiagolun EX;fucoidan YSK; caffeine; galactoarabinan; lion's mane mushroom extract;clerilys extract; extracts from Macrycystis Pyrifera; reishi mushroomextract; Pleurotus Ostreatus extract; Hypsizygus Ulmarius extract;Cladosiphon Okamuranus Extract; Acalypha Wilkesiana extract;Acanthopanax Gracilistylus extract; Allium Sativum extract; AnanusComosus extract; Cissampelos Sympodialis extract; Coriolus Versicolorextract; Echinacea Purpurea extract; Grifola Frondosa extract;Harpagophytum Procumbens extract; Panax Ginseng extract; PolygalaTenuifolia extract; Poria Cocos extract; Silybum Marianum extract;Smilax Glabra extract; Tinospora Cordifolia extract; Uncaria Tomentosaextract; Withania Somnifera extract; slime mold; Echinancea extract;Viscum Album extract; coffee robusta seed extract; capsaicin; ahexapeptide having the amino acid sequence (SEQ ID NO: 1)Val-Gly-Val-Ala-Pro-Gly (VGVAPG); ubiquitin; nicotinalides; cytochalasinB; and mixtures thereof; wherein the composition containing the combinedpathway inhibitors has an effectiveness in reducing the redness, pain,or heat that is equal to or greater than the identical compositioncontaining 1% hydrocortisone and being free of the combined pathwayinhibitors.